Quinuclidine derivatives and their use as muscarinic M3 receptor ligands

ABSTRACT

A compound according to formula (I)                    
     wherein: 
      is a phenyl ring, a C 4  to C 9  heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; 
     which shows high affinity for muscarinic M 3  receptors (Hm3).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from Spain application No. 9901580filed Jul. 14, 1999 and PCT application No. PCT/EP00/06469 filed Jul. 7,2000, the contents of each are incorporated herein by reference.

This invention relates to new therapeutically useful quinuclidinederivatives, to some processes for their preparation and topharmaceutical compositions containing them.

The novel structures according to the invention are antimuscarinicagents with a potent and long lasting effect. In particular, thesecompounds show high affinity for muscarinic M₃ receptors(Hm3).

In accordance with their nature as M₃ antagonists, the new compounds aresuitable for treating the following diseases: respiratory disorders suchas chronic obstructive pulmonary disease(COPD), chronic bronchitis,bronchial hyperreactivity, asthma and rhinitis; urological disorderssuch as urinary incontinence, pollakinuria in neuripenia pollakinuria,neurogenic or unstable bladder, cystospasm and chronic cystitis; andgastrointestinal disorders such as irritable bowel syndrome, spasticcolitis, diverticulitis and peptic ulceration.

The compounds claimed are also useful for the treatment of therespiratory diseases detailed above in association with β₂ agonists,steroids, antiallergic drugs or phosphodiesterase IV inhibitors.

Compounds of the present invention may also be expected to haveanti-tussive properties.

Depending on their nature the new compounds may be suitable for treatingvagally induced sinus bradycardia.

Compounds with related structures have been described as anti-spasmodicsand anti-cholinergic agents in several patents.

For example, in patent FR 2012964 are described quinuclidinolderivatives of the formula:

in which R is H, OH or an alkyl group having 1 to 4 carbon atoms; R₁ isa phenyl or thienyl group; and R₂ is a cyclohexyl, cyclopentyl orthienyl group, or, when R is H, R₁ and R₂ together with the carbon atomto which they are attached, form a tricyclic group of the formula:

in which X is —O—, —S— or —CH₂—, or an acid addition or quaternaryammonium salt thereof.

EP-418716 describes thienyl carboxylate esters of formula

wherein A is a group

m and n=1 or 2

Q is a —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH═CH—, group

Q′ is a ═NR or NRR═ group; R₁ is a thienyl, phenyl, furyl, cyclopentylor cyclohexyl group, optionally substituted; R₂ is H, OH, C₁-C₄ alkoxyor C₁-C₄ alkyl and R_(a) is H, F, Cl, CH₃— or —NR.

U.S. Pat. No. 5,654,314 describes compounds of formula:

wherein R is an optionally halo- or hydroxy-substituted C₁₋₄ alkylgroup; R is a C₁₋₄ alkyl group; or R and R═ together form a C₄₋₆alkylene group; X⁻ is an anion; and R₁ is H, OH, —CH₂OH, C₁₋₄ alkyl orC₁₋₄ alkoxy.

The present invention provides new quinuclidine derivatives with potentantagonist activity at muscarinic M₃ receptors which have the chemicalstructure described in formula (I):

wherein:

is a phenyl ring, a C₄ to C₉ heteroaromatic group containing one or moreheteroatoms (preferably selected from nitrogen, oxygen and sulphuratoms), or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenylgroup;

R¹, R² and R³ each independently represent a hydrogen or halogen atom,or a hydroxy group, or a phenyl, —OR⁴, —SR⁴, —NR⁴R⁵, —NHCOR⁴, —CONR⁴R⁵,—CN, —NO₂, —COOR⁴ or —CF₃ group, or a straight or branched lower alkylgroup which may optionally be substituted, for example, with a hydroxyor alkoxy group, wherein R⁴ and R⁵ each independently represent ahydrogen atom, straight or branched lower alkyl group, or together forman alicyclic ring; or R¹ and R² together form an aromatic, alicyclic orheterocyclic ring;

n is an integer from 0 to 4;

A represents a —CH₂—, —CH═CR⁶—, —CR⁶═CH—, —CR⁶R⁷—, —CO—, —O—, —S—,—S—(O)—, SO₂ or —NR⁶— group, wherein R⁶ and R⁷ each independentlyrepresent a hydrogen atom, straight or branched lower alkyl group, or R⁶and R⁷ together form an alicyclic ring;

m is an integer from 0 to 8; provided that when m=0, A is not —CH₂—;

p is an integer from 1 to 2 and the substitution in the azoniabicyclicring may be in the 2, 3 or 4 position including all possibleconfigurations of the asymmetric carbons;

B represents a group of formula i) or ii):

 wherein R¹⁰ represents a hydrogen atom, a hydroxy or methyl group; andR⁸ and R⁹ each independently represents

 wherein R¹¹ represents a hydrogen or halogen atom, or a straight orbranched lower alkyl group and Q represents a single bond, —CH₂—,—CH₂—CH₂—, —O—, —O—CH₂—, —S—, —S—CH₂— or —CH═CH—, and when i) or ii)contain a chiral centre they may represent either configuration; Xrepresents a pharmaceutically acceptable anion of a mono or polyvalentacid.

In the quaternary ammonium compounds of the present inventionrepresented by formula (I) an equivalent of an anion (X⁻)is associatedwith the positive charge of the N atom. X⁻ may be an anion of variousmineral acids such as, for example, chloride, bromide, iodide, sulfate,nitrate, phosphate, and organic acids such as, for example, acetate,maleate, fumarate, citrate, oxalate, succinate, tartrate, malate,mandelate, methanesulfonate and p-toluenesulfonate. X⁻ is preferably ananion selected from chloride, bromide, iodide, sulphate, nitrate,acetate, maleate, oxalate or succinate. More preferably X⁻ is chloride,bromide or trifluoroacetate.

The compounds of the present invention represented by the formula (I)described above, which may have one or more assymetric carbons, includeall the possible stereoisomers. The single isomers and mixtures of theisomers fall within the scope of the present invention.

If any of R¹ to R⁷ or R¹¹ represents an alkyl group, it is preferredthat said alkyl group contains 1 to 8, preferably 1 to 6 and morepreferably 1 to 4 carbon atoms. In particular it is preferred that anyalkyl group is represented by a methyl, ethyl, propyl, includingi-propyl, butyl including a n-butyl, sec-butyl and tert-butyl.

The alicyclic and heterocyclic rings mentioned in relation to formula(I) preferably comprise from 3 to 10, preferably from 5 to 7 members.The aromatic rings mentioned in relation to formula (I) above preferablycontain from 6 to 14, preferably 6 or 10 members.

Preferred compounds of formula (I) are those wherein represents aphenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl orbenzothiazolyl group, in particular a phenyl, pyrrolyl, or thienylgroup; R¹, R² and R³ each independently represent a hydrogen or halogenatom, or a hydroxyl, methyl, tert-butyl, —CH₂OH, 3-hydroxypropyl, —OMe,—NMe₂, —NHCOMe, —CONH₂, —CN, —NO₂, —COOMe or —CF₃ group, in particular ahydrogen atom, a hydroxy group or a halogen atom, wherein the halogenatom is preferably fluorine; n=0 or 1; m is an integer from 1 to 6,particularly 1, 2 or 3; A represents a —CH₂—, —CH═CH—, —CO—, —NH—,—NMe—, —O— or —S— group, in particular a —CH₂—, —CH═CH— or —O— group.

It is also preferred that p=2 and the substituent group —OC(O)B attachedto the azoniabicyclo[2.2.2]octane is at the 3 position, preferablyhaving the (R) configuration.

Further preferred compounds of formula I are those wherein B is a groupof formula i) or ii) as defined above wherein, if B is a group offormula (i), R⁸ and R⁹ each independently represent a phenyl, 2-thienyl,3-thienyl, 2-furyl or 3-furyl group, wherein R¹¹ is hydrogen atom; and,if B is a group of formula (Ii), Q represents a single bond, —CH₂—,—CH₂—CH₂—, —O— or —S— group, in particular a single bond, —CH₂—,—CH₂—CH₂— or —O— group, most preferably a single bond or —O— group; andin any case R¹⁰ is a hydrogen atom or a hydroxy or methyl group; andwhen i) or ii) contain a chiral centre they may represent either the (R)or the (S) configuration.

Most preferably the —OC(O)B group in formula (I) is diphenylacetoxy,2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy,-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy,9-hydroxy-9[H]-fluorene-9-carbonyloxy,9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,9-hydroxy-9[H]-xanthene-9-carbonyloxy,9-methyl-9[H]-xanthene-9-carbonyloxy,2,2-bis(4-fluorophenyl)-2-hydroxyacetoxy,2-hydroxy-2,2-di-p-tolylacetoxy, 2,2-difuran-2-yl-2-hydroxy acetoxy,2,2-dithien-2-ylpropionyloxy, 9,10-dihydroanthracene-9-carbonyloxy, 9[H]-thioxanthene-9-carbonyloxy, or5[H]-dibenzo[a,d]cycloheptene-5-carbonyloxy. Especially preferredcompounds are those wherein the —OC(O)B group in formula (I) isdiphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy,2,2-diphenylpropionyloxy, 2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy,9-hydroxy-9[H]-fluorene-9-carbonyloxy,9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,9-hydroxy-9[H]-xanthene-9-carbonyloxy or9-methyl-9[H]-xanthene-9-carbonyloxy.

The most preferred compounds of formula (I) are those wherein theazoniabicyclo group is substituted on the nitrogen atom with a3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl,3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl,2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl,3(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl,3-(2,4,6-trimethylphenoxy)propyl,3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl,3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl, 3-(naphthalen-2-yloxy)propyl, 3-(naphthalen-1-yloxy)propyl, 3-(2-chlorophenoxy)propyl,3-(2,4-difluorophenoxy)propyl, 3-(3-trifluoromethyl phenoxy)propyl,3-(3-cyanophenoxy)propyl, 3-(4-cyanophenoxy)propyl,3-(3-methoxyphenoxy)propyl, 3-(4-methoxyphenoxy)propyl,3-(benzo[1,3]dioxol-5-yloxy)propyl, 3-(2-carbamoylphenoxy)propyl,3-(3-dimethylaminophenoxy)propyl, 3-(4-nitrophenoxy)propyl,3-(3-nitrophenoxy)propyl, 3-(4-acetylaminophenoxy)propyl,3-(3-methoxycarbonylphenoxy)propyl, 3-[4-(3-hydroxypropyl)phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl,3-(3-hydroxymethylphenoxy) propyl, 3-(4-hydroxymethylphenoxy)propyl,3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl,3-(3-hydroxyphenoxy)propyl, 4-oxo-4-thien-2-ylbutyl,3-(1-methyl-[lH]-imidazol-2-ylsulfanyl)propyl,3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl,6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, or 2-benzyloxyethyl group.Especially preferred compounds are those wherein the azoniabicyclo groupis substituted on the nitrogen atom with a 3-phenoxypropyl,2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl,3-[2-hydroxyphenoxy]propyl, 3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl,3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group.

The following compounds are intended to illustrate but not to limit thescope of the present invention.

3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane;bromide

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane;bromide

3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane;bromide

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;chloride

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-bicyclo[2.2.2]octane;trifluoroacetate

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane; bromide

1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane;bromide

The present invention also provides processes for preparing compounds offormula (I).

The quaternary ammonium derivatives of general Formula I, may beprepared by reaction of an alkylating agent of general Formula II withcompounds of general Formula III. In Formulas I, II and III, R¹, R², R³,, A, X, B, n, m and p are as defined above.

This alkylation reaction may be carried out by two differentexperimental procedures, a) and b) which are described below. Inparticular method b) provides a new experimental process, using solidphase extraction methodologies, that allows the parallel preparation ofseveral compounds. Methods a) and b) are described in the experimentalsection. Compounds of general Formula II which are not commerciallyavailable have been prepared by synthesis according to standard methods.For example, compounds wherein n=0 and A=—O—, —S— or —NR⁶ ₁ wherein R⁶is as defined above, were obtained by reaction of the correspondingaromatic derivative or its potassium salt with an alkylating agent ofgeneral formula Y—(CH₂)m-X, wherein X may be a halogen and Y may be ahalogen or a sulphonate ester. In other examples, compounds of generalFormula II, where n>=1 were synthesised from the corresponding alcoholderivative of general Formula IV by known methods.

Compounds of general Formula III may be prepared by three differentmethods c, d and e illustrated in the following scheme and detailed inthe experimental section.

Some compounds of general formula III where B is a group of formula i),R⁸ and R⁹ are as described above and R¹⁰ is a hydroxy group, may also beprepared from the glyoxalate esters of general formula VII by reactionwith the corresponding organometallic derivative.

Compounds of general formula VII may be prepared from the correspondingglyoxylic acids following the standard methods c, d and e describedabove and detailed in the experimental section. The glyoxalatederivatives of formula VII where R⁸ is a 2-thienyl or 2-furyl group havenot been described before.

The following compounds are examples of compounds of general formula IIIand VII which have not been described before:

9-Methyl-9[H]-fluorene-9-carboxylic acid 1-azabicyclo[2.2.2]oct-3(R)-ylester (intermediate I-1c);

9-Methyl-9[H]-xanthene-9-carboxylic acid 1-azabicyclo[2.2.2]oct-3(R)-ylester (intermediate I-1d);

2-Hydroxydithien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester(intermediate I-4a).

Oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester(intermediate I-4b).

Oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester(intermediate I-4 g).

Oxofuran-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester(intermediate I-4e).

2-Hydroxy-2,2-difuran-2-yl-acetic acid

1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4d).

Compounds of Formula V could be:

4-hydroxy-1-azabicyclo[2.2.1]heptane, described in WO150080

4-hydroxy-1-azabicyclo[2.2.2]octane, described in Grob, C. A. et. al.Helv. Chim. Acta (1958), 41, 1184-1190

3(R)-hydroxy-1-azabicyclo[2.2.2]octane or3(S)-hydroxy-1-azabicyclo[2.2.2]octane, described in Ringdahl, R. ActaPharm Suec. (1979), 16, 281-283 and commercially available from CUChemie Uetikon GmbH.

The following examples are intended to illustrate, but not to limit, theexperimental procedures that have been described above.

The structures of the prepared compounds were confirmed by ¹H-NMR andMS. The NMR were recorded using a Varian 300 MHz instrument and chemicalshifts are expressed as parts per million (δ) from the internalreference tetramethyl silane. Their purity was determined by HPLC, usingreverse phase chromatrography on a Waters instrument, with valuesgreater than 95% being obtained. Molecular ions were obtained byelectrospray ionization mass spectometry on a Hewlett Packardinstrument.

Method-a

EXAMPLE 20 Preparation of 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, Bromide

200 mg of (Furan-2-yl)-hydroxy-phenylacetic acid1-aza-bicyclo[2.2.2]oct-3(R)-yl ester (0.6 mmol) were suspended in 4 mlof CH3CN and 6 ml of CHCl3. To this suspension were added 0.48 ml (3mmol) of 3-phenoxypropyl bromide. After stirring for 72 h at roomtemperature in inert atmosphere, solvents were evaporated. Ether wasadded and the mixture stirred. The solid obtained was filtered andwashed several times with ether. The yield was 0.27 g (83%) of titlecompound as a mixture of diastereomers.

¹H-NMR (DMSO-d6): δ 1.50-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H),3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.25-6.35(double dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m,1H); MS [M-Br]⁺: 462; mp 166° C.

Method-b

EXAMPLE 51 Preparation of 3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

60 mg (0.17 mmols) of hydroxy-dithien-2-yl-acetic acid1-aza-bicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 1 ml of dmso. Tothis solution 188 mg (0.85 mmol) of 3-(naphthalen-1-yloxy)-propylchloride were added. After stirring overnight at room temperature, themixture was purified by solid phase extraction with a cation exchangeMega Bond Elut cartridge, previously conditioned at pH=7.5 with 0.1 MNaH2PO4 buffer. The reaction mixture was applied to the cartridge andwashed first with 2 ml of DMSO and then three times with 5 ml of CH3CN,rinsing away all starting materials. The ammonium derivative was elutedwith 5 ml of 0.03 M TFA solution in CH3CN:CHCl3 (2:1). This solution wasneutralized with 300 mg of poly(4-vinylpyridine), filtered andevaporated to dryness.

The yield was 17 mg (15%) of title compound. ¹H-NMR (DMSO-d6): δ 1.7-2.1(m, 4H), 2.2-2.4 (m, 3H), 3.2-3.6 (m, 7H), 4.0 (m, 1H), 4.2 (t, 2H),5.25 (m, 1H), 7.0 (m 3H), 7.2 (m, 2H), 7.4-7.6 (m, 7H), 7.85 (d, 1H),8.2 (d, 1H); MS [M-CF₃COO]⁺: 534.

Method-c

Methyl ester derivatives of general Formula VI were prepared by standardmethods of esterification from the corresponding carboxylic acid orfollowing the procedures described in examples I-1e, I-1f and I-1g oraccording to procedures described in literature: FR 2012964; Larsson. Let al. Acta Pharm. Suec. (1974), 11(3), 304-308; Nyberg, K. et. al. ActaChem. Scand. (1970), 24, 1590-1596; and Cohen, V. I. et. al. J. Pharm.Sciences (1992), 81, 326-329.

EXAMPLE I-1a Preparation of (Furan-2-yl)hydroxyphenylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

3.24 g (0.014 mols) of (Furan-2-yl)-hydroxy-phenylacetic acid methylester were dissolved in 85 ml of toluene. To this solution were added2.08 g (0.016 mols) of 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane and 0.224g (5.6 mmols) of HNa (60% dispersion in mineral oil). The mixture wasrefluxed with continuous removal of distillate and when necessaryreplacement with fresh toluene for 1.5 hours. The cooled mixture wasextracted with 2N HCl acid, the aqueous layer washed with ethyl acetate,basified with K2CO3 and extracted with CHCl3. The organic layer wasdried over Na2SO4 and evaporated. The oil obtained (3.47 g) crystallisedafter cooling at room temperature. This solid was suspended in hexaneand filtered. The yield was 2.5 g (54%) of a mixture of diasteroisomers,mp: 140-142° C.; GC/MS [M]⁺: 327; ¹H-NMR (CDCl3): δ 1.20-1.70 (m, 4H),1.90-2.10 (m, 1H), 2.45-2.80 (m, 5H), 3.10-3.30 (m, 1H), 4.8 (bs, OH),4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H),7.60-7.70 (m, 2H).

After four crystallizations of 0.5 g of this mixture from boilingacetonitrile, 0.110 g of a pure diastereomer(I) were obtained. From themother liquors of crystallization was obtained the other diastereomer(2). (*:configuration not assigned). Diastereomer 1 was hydrolysed toyield (+)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pureenantiomer, [α]²⁵ _(D)=+5.6 (c=2, EtOH). Diastereomer 2 was hydrolysedto yield (−)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pureenantiomer, [γ]²⁵ _(D)=−5.7 (c=2, EtOH).

Diastereomer 1: 2(*)—(Furan-2-yl)hydroxyphenylacetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester.

¹H-NMR (CDCl3): δ 1.20-1.70 (m, 4H), 1.90 (m, 1H), 2.45-2.50 (m, 1H),2.50-2.80 (m, 4H), 3.10-3.20 (m, 1H), 4.8 (bs, OH), 4.90-5.0 (m, 1H),6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H), 7.60-7.70 (m, 2H).

Diastereomer 2: 2(*)—(Furan-2-yl)hydroxyphenylacetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester.

¹H-NMR (CDCl3): δ 1.20-1.70 (m, 4H), 2.10 (m, 1H), 2.50-2.80 (m, 5H),3.20-3.30 (m, 1H), 4.8 (bs, OH), 4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35(m, 1H), 7.30-7.50 (m, 4H), 7.60-7.70 (m, 2H).

EXAMPLE I-1b Preparation of Furan-2-ylhydroxythien-2-ylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

Prepared as in example I-1a. The yield was 3.06 g (64.3%) of a mixtureof diastereoisomers, mp: 1721C; GC/MS [M]⁺: 333; ¹H-NMR (DMSO-d6): δ1.21-1.27 (m, 1H), 1.41-1.60 (m, 3H), 1.87 (m, 1H), 2.36-2.69 (m, 5H),3.02-3.14 (m, 1H), 4.75-4.82 (m, 1H), 6.24-6.25 (m, 1H), 6.42-6.45 (m,1H), 7.01-7.06 (m, 1H), 7.11-7.14 (m, 2H), 7.51-7.54 (m, 1H), 7.66-7.69(m, 1H).

EXAMPLE I-1c Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

Prepared as in example I-1a. The yield was 3.34 g of an oil (80%). Thisproduct was solidified by formation of the oxalate salt (1:1), mp:1861C. MS [M free base+1]⁺: 334.

Oxalate salt, ¹H-NMR (DMSO-d6): δ 1.43-1.55 (m, 2H), 1.68-1.78 (m, 2H),1.75 (s, 3H), 2.02 (m, 1H), 2.70-2.90 (m, 1H), 2.92-3.15 (m, 4H),3.50-3.57 (m, 1H), 4.88 (m, 1H), 7.35-7.47 (m, 4H), 7.62-7.70 (m, 2H),7.89-7.91 (m, 2H).

EXAMPLE I-1d Preparation of 9-Methyl-9[H]-xanthene-9-carboxylic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

Prepared as in example I-1a. The yield was 1.91 g of an oil (53%). Thisproduct was solidified by formation of the oxalate salt (1:1), mp:1521C. MS [M free base+1]⁺: 350.

Oxalate salt, ¹H-NMR (DMSO-d6): δ 1.20-1.30 (m, 1H), 1.40-1.52 (m, 1H),1.64-1.81 (m, 2H), 1.90 (s, 3H), 2.0 (m, 1H), 2.53-2.66 (m, 1H),2.71-2.76 (m, 1H), 2.97-3.10 (m, 3H), 3.44-3.52 (m, 1H), 4.90-4.92 (m,1H), 7.12-7.18 (m, 4H), 7.32-7.38 (m, 2H), 7.43-7.48 (m, 2H), 8.0-9.8(bs, 1H, H+).

EXAMPLE I-1e Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic AcidMethyl Ester

Lithium diisopropylamide (26.7 ml of a 2M solution inheptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a stirredsolution of 9[H]-fluorene-9-carboxylic acid (5 g, 0.0237 mol) in THF (70ml) at between 0 and 51C in N₂ atmosphere. The mixture was warmed toroom temperature and refluxed 1.5 hours. The reaction mixture was cooledto room temperature and a solution of CH3I (1.85 ml, 0.03 mol) in THF(1.85 ml) was added. The mixture was stirred overnight at roomtemperature and evaporated. To the residue in MeOH (70 ml) was addedconcentrated sulfuric acid (3.9 ml) in MeOH (25 ml), the mixture wasrefluxed for 2 hours and evaporated. The residue was partitioned betweenchloroform and saturated K2CO3 solution. The aqueous layer was extractedagain with chloroform and the organic layers were combined, washed withwater, dried over sodium sulphate and evaporated to dryness to obtain5.73 g of a brown oil. This product was purified by columnchromatography (silica gel, hexane/ethyl acetate 95:5) to yield 4.43 g(78.5%) of a pure product, structure confirmed by ¹H-NMR.

¹H-NMR (CDCl3): δ 1.80 (s, 3H), 3.60 (s, 3H), 7.50-7.65 (m, 4H), 7.75(m, 2H), 8.0 (m, 2H).

EXAMPLE I-1f Preparation of 9-Methyl-9[H]-xanthene-9-carboxylic AcidMethyl Ester

Prepared as in example I-1e. The yield was 2.65 g (47.2%). ¹H-NMR(CDCl3): δ 1.90 (s, 3H), 3.6 (s, 3H), 7.05-7.35 (m, 8H).

EXAMPLE I-1g Preparation of 9-Hydroxy-9[H]-xanthene-9-carboxylic AcidMethyl Ester

Lithium diisopropylamide (20.3 ml of a 2M solution inheptane/tetrahydrofurane/ethylbenzene, 0.041 mol) was added to a stirredsolution of 7 g (0.029 mol) of 9[H]-xantene-9-carboxylic acid methylester (prepared by a standard method) in THF (70 ml) at between 0 and51C in N₂ atmosphere. The mixture was stirred 1 h at this temperatureand then was added by N2 pressure to a dry solution of oxygen in etherat 01C. After 30 min, an equal volum of NaHSO3, 40% aqueous solution,was added, and the reaction mixture was warmed to room temperature andstirred for 30 min. The two layers were separated and the aqueous phasewas extracted twice with ethyl acetate. The organic phases werecombined, treated with NaHSO3 (40% aqueous solution), washed with water,dried over sodium sulphate and evaporated to dryness to obtain 8.89 g ofa brown solid.

This procedure was repeated with 5 g of starting material yielding 6.049of the same brown solid.

The products were combined and purified by column chromatography (silicagel, hexane/ethyl acetate 90:10) to yield 7.60 g (global Rt: 59.4%) of apure product, structure confirmed by ¹H-NMR.

¹H-NMR (DMSO-d6): δ 3.5 (s, 3H), 7.0 (s, 1H, OH), 7.2 (m, 4H), 7.4 (m,2H), 7.55 (m, 2H).

Method-d

EXAMPLE I-2a Preparation of10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic Acid1-azabicyclo[2.2.2]oct-3-(R)-yl Ester

2.15 g of 10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid(9.0 mmol) were dissolved in 40 ml of CHCl3 (ethanol free). The solutionwas cooled at 0° C. and 0.86 ml of oxalyl chloride (9.9 mmols) and adrop of DMF were added. The mixture was stirred and allowed warm to roomtemperature. After an hour at this temperature the solvents wereevaporated and the residue was dissolved in CHCl3 and evaporated again.This procedure was repeated two times. The obtained oil was dissolved in20 ml of toluene and added to a solution of 1.26 g (9.9 mmol) of3-(R)-hydroxy-1-azabicyclo[2.2.2]octane in 40 ml of hot toluene. Thereaction mixture was refluxed for 2 hours. After cooling the mixture wasextracted with 2N HCl acid. The aqueous layer was basified with K2CO3and extracted with CHCl3. The organic layer was dried over Na2SO4 andevaporated to dryness. The residue was purified by column chromatography(silica gel, CHCl3:MeOH:NH40H, 95:5:0.5). The yield was 1.5 g (48%); mp:112-113° C.; CG/MS [M]⁺: 347; ¹H-NMR (CDCl3): δ 1.10-1.35 (m, 2H),1.40-1.52 (m, 1H), 1.52-1.68 (m, 1H), 1.90 (m, 1H), 2.40-2.60 (m, 2H),2.60-2.77 (m, 3H), 2.83-2.96 (m, 2H), 3.07-3.19 (m, 1H), 3.25-3.40 (m,2H), 4.80 (m, 2H), 7.10-7.30 (m, 8H).10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid wasprepared as described in Kumazawa T. et al., J. Med. Chem., (1994), 37,804-810.

EXAMPLE I-2b Preparation of 5[H]-Dibenzo[a,d]cycloheptene-5-carboxylicAcid 1-azabicyclo[2.2.2]oct-3-(R)-yl Ester

Prepared as in example I-2a. The yield was 3.12 g (71%); mp 1291C; MS[M+1]⁺: 346; ¹H-NMR (DMSO-d6): δ 0.90-1.10 (m, 2H), 1.30-1.50 (m, 2H),1.58 (m, 1H), 2.21-2.26 (m, 2H), 2.47-2.50 (m, 3H), 2.86-2.94 (m, 1H),4.48-4.51 (m, 1H), 5.33 (s, 1H), 7.0 (m, 2H), 7.29-7.43 (m, 6H),7.49-7.51 (m, 2H).

5[H]-Dibenzo[a,d]cycloheptene-5-carboxylic acid was prepared asdescribed in M. A. Davis et al; J. Med. Chem., (1964), Vol 7, 88-94.

EXAMPLE I-2c Preparation of 9,10-Dihydroanthracene-9-carboxylic Acid1-azabicyclo[2.2.2]oct-3-(R)-yl Ester

Prepared as in example I-2a. The yield was 0.77 g (62.6%); mp 1391C; MS[M+1]⁺: 334; ¹H-NMR (DMSO-d6): δ 1.1-1.2 (m, 1H), 1.25-1.40 (m, 2H),1.40-1.55 (m, 1H), 1.73 (m, 1H), 2.20 (m, 1H), 2.35-2.65 (m, 4H),2.90-2.98 (m, 1H), 3.93-4.14 (dd, 2H, J=1.8 Hz, J=4.3 Hz), 4.56 (m, 1H),5.14 (s, 1H), 7.25-7.35 (m, 4H), 7.35-7.50 (m, 4H).

9,10-Dihydro-anthracene-9-carboxylic acid was prepared as described inE. L. May and E. Mossettig; J. Am. Chem. Soc., (1948), Vol 70, 1077-9.

Method-e

EXAMPLE I-3 Preparation of 2,2-Diphenylpropionic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

1.1 g (4.8 mmol) of 2,2-diphenylpropionic acid were dissolved in 20 mlof THF. To this solution were added 0.87 g (5.3 mmol) of1,1=-carbonyldiimidazole and the mixture was refluxed for an hour. Thereaction was monitored by TLC following the formation of theimidazolide. When the reaction was completed part of the solvent wasevaporated and 0.67 g (5.3 mmol) of3-(R)-hydroxy-1-azabicyclo[2.2.2]octane were added. The reaction mixturewas refluxed for 16 h, cooled, diluted with ether and washed with water.The organic layer was extracted with HCl 2N, the acid solution basifiedwith K2CO3 and extracted with CHCl3. The organic solution was dried overNa2SO4 and evaporated to dryness to yield 1.21 g (75.2%) of an oil thatwas identified as the title ester.

0.64 g (1.9 mmol) of 2,2-Diphenylpropionic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 6 ml of ketoneand 0.085 g(0.95 mmol) of oxalic acid were added. After slow addition ofether a white solid was formed. The yield was 0.33 g (45.6%) of oxalateof 2,2-Diphenyl-propionic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester; mp:1461C; MS [M free base+1]⁺: 336.

Oxalate salt, ¹H-NMR (CDCl3): δ 1.40-1.64 (m, 2H), 1.90 (s, 3H),1.80-2.0 (m, 2H), 2.31 (m, 1H), 2.73-2.85 (m, 1H), 3.0-3.10 (m, 1H),3.10-3.32 (m, 3H), 3.53-3.70 (m, 1H), 5.13 (m, 1H), 7.14-7.40 (m, 10H),9.25 (broad band, 2H, H+).

Method-f

EXAMPLE I-4a Preparation of 2-Hydroxy-2,2-dithien-2-ylacetic Acid1-azabicyclo[2.2.2]oct-4-yl Ester

A solution of 2-thienylmagnesium bromide was prepared from 220 mg (9mmols)of Magnesium and 0.86 ml (9 mmols) of 2-bromothiophene in 15 ml ofTHF. This solution was added to 1.95 g (7 mmols) of oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4b)dissolved in 20 ml of THF. The mixture was stirred at room temperaturefor 1 hour, refluxed for 1 hour, cooled, treated with a saturatedsolution of ammonium chloride and extracted with ether. After removal ofthe solvent the solid obtained was recrystallised from acetonitrile toyield 1.45 g, of a white solid (56%). ¹H-NMR (DMSO-d6): δ 1.80-2.0 (m,6H), 2.80-3.0 (m, 6H), 7.0 (m, 2H), 7.13 (m, 2H), 7.18 (s, 1H), 7.51 (m,2H); MS [M+1]: 350; mp 174° C.

EXAMPLE I-4b Preparation of Oxothien-2-yl-acetic Acid1-azabicyclo[2.2.2]oct-4-yl Ester

Oxalyl chloride (1.5 ml, 0.017 mol) was added to a solution ofoxothien-2-yl-acetic acid (2.24 g, 0,014 mol) and dimethylformamide (onedrop) in 30 ml of chloroform (etanol free) at 01C. The mixture wasstirred and allowed to warm at room temperature. After one hour thesolvent was evaporated. The residue was dissolved in chloroform andevaporated again. This procedure was repeated two times. The productobtained was disolved in CHCl3 (30 ml) and added to a suspension of 1.1g (0.009 mols) of 4-hydroxy-1-azabicyclo[2.2.2]octane, 1.8 ml oftriethylamine (0,013 mols), 0.6 g (0.9 mmols) ofN-(methylpolystyrene)-4-(methylamino) pyridine at 70° C. The mixture wasrefluxed for 1 hour, cooled, filtered and washed with water. The titleproduct was extracted with a solution of diluted HCl, washed with CHCl3,basified with K2CO3 and extracted again with CHCl3. After removal of thesolvent 1.47 g (45%) of a solid was obtained. ¹H-NMR (dmso): δ 2.0 (m,6H), 2.9 (m, 6H), 7.35 (m, 1H), 8.05 (m, 1H), 8.3 (m, 1H).

EXAMPLE I-4c Preparation of (Furan-2-yl)hydroxyphenylacetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in THF),was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylaceticacid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolvedin 15 ml of THF, at −701C in N2 atmosphere. The mixture was stirred atthis temperature for 10 minuts, and then warmed to room temperature.After 1 hour, the reaction mixture was treated with a saturated solutionof ammonium chloride and extracted three times with ethyl acetate Theorganic phases were combined, washed with water and dried over Na2SO4.After removal of the solvent, the solid obtained was treated with etherand filtered to yield 0.67 g (40%) of a product whose structure wasconfirmed by ¹H-NMR. This compound was also prepared as is described inExample I-la (Method c). The diastereomers were separated bycrystallization from acetonitrile and distinguished by ¹H-NMR.

EXAMPLE I-4d Preparation of 2-Hydroxy-2,2-difur-2-yl-acetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

The title compound was synthesised as in example I-4c from intermediateI-4e—and 2-furanyl lithium which was prepared with furane and butyllithium following a standard method. The yield was 380 mg (8%). ¹H-NMR(CDCl3): δ 1.2-1.4 (m, 1H), 1.4-1.8 (m, 3H), 2.0 (m, 1H), 2.6-2.85 (m,5H), 3.2 (m, 1H), 5.0 (m, 1H), 6.4 (m, 3H), 7.3 (m, 1H), 7.5 (m, 2H). MS[M+1]⁺: 318.

EXAMPLE I-4e Preparation of Oxofuran-2-yl-acetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution ofoxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (onedrop) in 150 ml of chloroform (etanol free) at 01C. The mixture wasstirred and allowed to warm at room temperature. After five hours thesolvent was evaporated. The residue was dissolved in chloroform andevaporated again. This procedure was repeated two times. The productobtained was disolved in CHCl3 (150 ml) and a solution of3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added tothis at 01C. The mixture was stirred and allowed to warm at roomtemperature. After 15 h at r.t., the mixture was washed with 10% aqueouspotassium carbonate, then with water, dried over Na2SO4 and evaporatedto give 9.34 g (52.5%) of the title compound as a dark oil. Estructureconfirmed by NMR.

¹H-NMR (CDCl3): δ 1.40-1.60 (m, 1H), 1.60-1.80 (m, 2H), 1.80-2.05 (m,1H), 2.20 (m, 1H), 2.70-3.10 (m, 5H), 3.30-3.45 (m, 1H), 5.10 (m, 1H),6.7 (m, 1H), 7.7 (m, 1H), 7.8 (m, 1H).

EXAMPLE I-4f Preparation of 2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

The title compound was prepared as described in example I-4c fromintermediate I-4 g. The yield was 3 g (33%) as a mixture ofdiastereomers. After five crystallizations of 1.5 g of this mixture fromboiling isopropanol, 0.200 g of a pure diastereomer(1) were obtained.The mother liquors from first crystallization were enriched with theother diastereomer (2). Diastereomer 1 was hidrolysed to yield(+)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid as a pure enantiomer,[α]²⁵ _(D)=+25.4 (c=2, EtOH). This value was assigned to the Rconfiguration provided that in literature (A. I. Meyers et. al. J. Org.Chem.(1980), 45(14), 2913) the 2(S) enantiomer has been described whith[α]²⁵ ^(D)=−20 (c=2, EtOH).

Diastereomer 1: 2(R)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester.

¹H-NMR (DMSO-d6): δ 1.1-1.25 (m, 1H), 1.3-1.6 (m, 3H), 1.83 (m, 1H),2.4-2.7 (m, 5H), 3.1 (m, 1H), 4.8 (m, 1H), 7.0 (m, 2H), 7.05 (m, 1H),7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5 (m, 1H).

Diastereomer 2: 2(S)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid 1-azaBicyclo[2.2.2]oct-3(R)-yl Ester.

¹H-NMR (DMSO-d6): δ 1.1-1.25 (m, 1H), 1.4-1.6 (m, 3H), 1.9 (m, 1H),2.3-2.7 (m, 5H), 3.05 (m, 1H), 4.8 (m, 1H), 7.0 (m, 2H), 7.05 (m, 1H),7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5 (m, 1H).

EXAMPLE I-4g Preparation of Oxothien-2-yl-acetic Acid1-azabicyclo[2.2.2]oct-3(R)-yl Ester

Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution ofoxothien-2-yl-acetic acid (2 g, 0,0128 mol) and dimethylformamide (onedrop) in 30 ml of chloroform (etanol free) at 01C. The mixture wasstirred and allowed to warm at room temperature. After one hour thesolvent was evaporated. The residue was dissolved in chloroform andevaporated again. This procedure was repeated two times. The productobtained was disolved in CHCl3 (30 ml) and a solution of3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added tothis at 01C. The mixture was stirred and allowed to warm at roomtemperature. After 1.5 h at r.t., the mixture was washed with 10%aqueous potassium carbonate, then with water, dried over Na2SO4 andevaporated to give 3.14 g (92.6%) of the title compound as a yellow oil.¹H-NMR (CDCl3): δ 1.40-1.50 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.80 (m,1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05 (m, 5H), 3.30-3.40 (m,1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H), 8.10 (m, 1H).

Other carboxylic acids of Formula B—C(O)OH, whose preparation (or thesyntheses of their derivatives methyl ester, chloride or imidazolide)have not been described in methods c, d, e or in the Examples I-1e, 1-1fand I-1g, and that are not commercially available, could be prepared asis described in the following references:

FR 2012964

M. A. Davis et al; J. Med. Chem. (1963), 6, 513-516.

T. Kumazawa et al; J. Med. Chem, (1994), 37(6), 804-810.

M. A. Davis et al; J. Med. Chem., (1964), Vol (7), 88-94.

Sestanj, K; Can. J. Chem., (1971), 49, 664-665.

Burtner, R.; J. Am. Chem. Soc., (1943), 65, 1582-1585

Heacock R. A. et al.; Ann. Appl. Biol., (1958), 46(3), 352-365.

Rigaudy J. et. al.; Bull. Soc. Chim. France, (1959), 638-43.

Ueda I. et al.; Bull. Chem. Soc. Jpn; (1975), 48 (8), 2306-2309.

E. L. May et. al.; J. Am. Chem. Soc., (1948), 70, 1077-9.

Also included within the scope of the present invention arepharmaceutical composition which comprise, as the active ingredient, atleast one quinuclidine derivative of general formula (I) in associationwith a pharmaceutically acceptable carrier or diluent. Preferably thecomposition is made up in a form suitable for oral administration.

The pharmaceutically acceptable carrier or diluents which are mixed withthe active compound or compounds, to form the composition of thisinvention are well-known per se and the actual excipients used dependinter alia on the intended method of administration of the composition.

Compositions of this invention are preferably adapted for oraladministration. In this case, the composition for oral administrationmay take the form of tablets, film-coated tablets, liquid inhalant,powder inhalant and inhalation aerosol; all containing one or morecompounds of the invention; such preparations may be made by methodswell-known in the art.

The diluents which may be used in the preparations of the compositionsinclude those liquid and solid diluents which are compatible with theactive ingredient, together with colouring or flavouring agents, ifdesired. Tablets or film-coated tablets may conveniently contain between500 and 1 mg, preferably from 5 to 300 mg of active ingredient. Theinhalant compositions may contain between 1 Φg and 1,000 Φg, preferablyfrom 10 to 800 Φg of active ingredient. In human therapy, the dose ofthe compound of general formula (I) depend on the desired effect andduration of treatment; adult doses are generally between 3 mg and 300 mgper day as tablets and 10 Φg and 800 Φg per day as inhalant composition.

Pharmacological Action

The following examples demonstrate the excellent pharmacologicalactivities of the compounds of the present invention. The results onhuman muscarinic receptors binding and in the test on bronchospasm inguinea pig, were obtained as described below.

Human Muscarinic Receptor Studies.

The binding of [³H]-NMS to human muscarinic receptors was performedaccording to Waelbroek et al (1990) (1). Assays were carried out at 25°C. Membrane preparations from stably transfected chinese hamsterovary-K1 cells (CHO) expressing the genes for the human muscarinicreceptors Hm3 were used.

For determination of IC₅₀, membrane preparations were suspended in DPBSto a final concentration of 89 μg/ml for the Hm3 subtype. The membranesuspension was incubated with the tritiated compound for 60 min. Afterincubation the membrane fraction was separated by filtration and thebound radioactivity determined. Non specific binding was determined byaddition of 10⁻⁴ M atropine. At least six concentrations were assayed induplicate to generate individual displacement curves.

COMPOUNDS BINDING TO RECEPTOR No M₃ (IC₅₀ nM) ATROPINE 3.2 IPRATROPIUM3.0 1 31 2 15 7 22 8 4.8 17 14 18 6.6 20 6.8 35 13 36 2.7 39 3.8 44 4.453 5.6 71 8.2 74 16 77 3.1 78 5 84 9.9 89 5.4 99 31 100 14 101 7.6 10931 114 14 116 23 126 13 127 16 128 8.8 129 6.3 136 11 137 6.9 138 19 14613

(1) M. Waelbroek, M. Tastenoy, J. Camus, J Christophe. Binding ofselective antagonists to four muscarinic receptors (M1 to M4) in ratforebrain. Mol. Pharmacol. (1990) 38: 267-273.

Our results show that the compounds of the present invention haveaffinities for the M₃ receptors which are very similar to the referencecompounds.

The compounds of the invention preferably have high affinities formuscarinic M₃ receptors (HM3), preferably human muscarinic receptors.Affinity levels can typically be measured by in vitro assays, forexample, as described above.

Preferred compounds of the invention have an IC₅₀ (nM) value for M₃receptors of less than 35, preferably less than 25,20 or 15, morepreferably less than 10, 8 or 5.

Test on Bronchospasm in Guinea Pig

The studies were performed according to Konzett and Rössler (2). Aqueoussolutions of the agents to be tested were nebulized and inhaled byanaesthetized ventilated male guinea pigs (Dunkin-Hartley). Thebronchial response to intravenous acetylcholine challenge was determinedbefore and after drug administration and the percent change in pulmonaryresistance at several time-points.

2. Konzett H., Rössler F. Versuchsanordnung zu Untersuchungen anderbronchialmuskulatur. Arch. Exp. Path. Pharmacol. 195: 71-74 (1940)

The compounds of the present invention inhibited the bronchospasmresponse to acetylcholine with high potency and a long duration ofaction.

From the above described results one of ordinary skill in the art canreadily understand that the compounds of the present invention haveexcellent antimuscarinic activity (M₃) and thus are useful for thetreatment of diseases in which the muscarinic M₃ receptor is implicated,including respiratory diseases such as chronic obstructive pulmonarydisease, chronic bronchitis, asthma and rhinitis, urinary diseases suchas urinary incontinence and pollakinuria in neuripenia pollakinuria,neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm andchronic cystitis and gastrointestinal diseases such as irritable bowelsyndrome, spastic colitis and diverticulitis.

The present invention further provides a compound of formula (I) or apharmaceutically acceptable composition comprising a compound offormula(I) for use in a method of treatment of the human or animal bodyby therapy, in particular for the treatment of respiratory, urinary orgastrointestinal disease.

The present invention further provides the use of a compound of formula(I) or a pharmaceutically acceptable composition comprising a compoundof formula (I) for the manufacture of a medicament for the treatment ofrespiratory, urinary or gastrointestinal disease.

Further, the compounds of formula (I) and pharmaceutical compositionscomprising a compound of formula (I) can be used in a method of treatingrespiratory, urinary or gastrointestinal disease, which method comprisesadministering to a human or animal patient in need of such treatment aneffective amount of a compound of formula (I) or a pharmaceuticalcomposition comprising a compound of formula (I).

The present invention will be further illustrated by the followingexamples. The examples are given by way of illustration only and are notto be construed as limiting.

EXAMPLE 1

3(R)-Diphenylacetoxy-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 500 mg, 81%. ¹H-NMR (CDCl3): δ 1.72-2.18 (m,6H), 2.35 (m, 1H), 3.0 (m, 1H), 3.23 (m, 1H), 3.59-3.88 (m, 5H), 4.0 (m,2H), 4.30 (m, 1H), 5.1 (s, 1H), 5.25 (m, 1H), 6.8-6.9 (m, 2H), 6.9-7.0(m, 1H), 7.2-7.4 (m, 12H); MS [M-Br]⁺: 456; mp 129° C.

EXAMPLE 2

3(R)-(2-Hydroxy-2,2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 280 mg,42%. ¹H-NMR (DMSO-d6): δ 1.5-1.7 (m, 2H),1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 6H), 3.9-4.1 (m,3H), 5.25 (m, 1H), 6.8 (bs, OH), 6.95 (m, 3H), 7.2-7.5 (m, 12H); MS[M-Br]⁺: 472; mp 199° C.

EXAMPLE 3

3(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 400 mg,85%. ¹H-NMR (DMSO-d6): δ 1.5-1.65 (m,1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H), 2.05-2.2 (m, 2H), 2.3 (m, 1H),3.1-3.2 (m, 1H), 3.3-3.5 (m,6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.25 (m,1H), 6.9-7.0 (m, 4H), 7.1-7.5 (m, 10H); MS [M-Br]⁺: 508; mp 253° C.

EXAMPLE 4

3(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 300 mg,67%. ¹H-NMR (DMSO-d6): δ 1.5-1.65 (m,1H), 1.7-1.85 (m, 1H), 1.85-2.1 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H),3.15-3.25 (m, 1H), 3.3-3.6 (m, 6H), 3.95-4.05 (m, 1H), 5.25 (m, 1H),6.95 (s, OH), 7.1-7.5 (m, 13H); MS [M-Br]⁺: 478; mp 182° C.

EXAMPLE 5

3(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 500 mg, 54%. ¹H-NMR (DMSO-d6): δ 1.55-1.8 (m,2H), 1.85-2.0 (m, 2H), 2.05-1.15 (m, 2H), 2.3 (s, 7H), 3.05-3.15 (m,1H), 3.25-3.5 (m, 6H), 3.95 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 6.8 (s,OH), 6.95 (m, 3H), 7.1-7.2 (m, 4H), 7.2-7.35 (m, 6H); MS [M-Br]⁺: 500;mp 183° C.

EXAMPLE 6

3(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 650 mg, 74%. ¹H-NMR (DMSO-d6): δ 1.55-1.8 (m,2H), 1.85-2.05 (m, 2H), 2.25 (s, 7H), 2.9-3.05 (m, 2H), 3.1-3.25 (m,1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.8 (s, OH), 7.1-7.2(m, 4H), 7.2-7.35 (m, 9H); MS [M-Br]⁺: 470; mp 144° C.

EXAMPLE 7

3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods e and a. Theyield of final step was 250 mg, 61%. ¹H-NMR (CDCl3): δ 1.47-1.60 (m,1H), 1.8-2.0 (m, 1H), 2.0 (s, 3H), 2.0-2.15 (m, 4H), 2.39 (s, 1H), 2.6(m, 1H), 2.92 (d, 1H), 3.6 (m, 1H), 3.7-3.9 (m, 4H), 4.0 (m, 2H), 4.3(m, 1H), 5.25 (m, 1H), 6.85 (m, 2H), 7.0 (m, 1H), 7.3 (m, 12H); MS[M-Br]⁺: 470; mp 186° C.

EXAMPLE 8

3(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The yield of final step was 520 mg,62%.¹H-NMR (DMSO-d6): δ 1.5-1.95 (m, 4H), 2.1 (m, 2H), 2.3 (m, 1H), 3.1(m, 1H), 3.3-3.5 (m, 6H), 3.9 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 7.0(m, 4H), 7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m, 3H); MS [M-Br]⁺: 478; mp220° C.

EXAMPLE 9

3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 10 mg,23%. ¹H-NMR (DMSO-d6): δ 1.5-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0 (m,2H), 2.05-2.1 (m, 2H), 2.3 (m, 1H), 3.05-3.2 (m, 1H), 3.25-3.55 (m, 6H),3.85-3.95 (m, 1H), 4.0 (t, 2H), 5.2 (m, 1H), 6.95 (m, 3H), 7.03 (m, 1H),7.15 (dd, 1H), 7.2 (s, OH), 7.3-7.5 (m, 5H), 7.45-7.55 (m, 3H); MS[M-CF3COO]⁺: 478.

EXAMPLE 10

3(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 2. The yield of final step was 3 mg,11%. ¹H-NMR (DMSO-d6): δ 1.6-1.75 (m, 2H), 1.8-2.0 (m, 4H), 2.25 (m,1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m, 6H), 3.8-3.95 (m, 1H),5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.1 (dd, 1H), 7.18 (s,OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H), 7.51 (dd, 1H); MS [M-CF3COO]⁺:478.

EXAMPLE 11

3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 9 mg,22%. ¹H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.65-1.75 (m, 1H), 1.85-2.05(m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H), 3.1-3.25 (m, 1H), 3.25-3.55 (m,6H), 3.9-4.0 (m, 1H), 5.25 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 7.2 (m,1H), 7.25-7.4 (m, 8H), 7.45 (m, 2H, 7.55 (m, 1H); MS [M-CF3COO]⁺: 448.

EXAMPLE 12

3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 11 mg,26%. ¹H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.6-1.75 (m, 1H), 1.8-2.0(m, 4H), 2.25 (m, 1H), 2.55 (t, 2H), 3.0-3.1 (m, 1H), 3.15-3.55 (m, 6H),3.8-3.9 (m, 1H), 5.2 (m, 1H), 7.0 (m, 1H), 7.1 (m, 1H), 7.15-7.4 (m,9H), 7.45 (m, 2H), 7.5 (m, 1H); MS [M-CF3COO]⁺: 462.

EXAMPLE 13

3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 10 mg,24%. ¹H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0(m, 2H), 2.3 (m, 1H), 3.1-3.6 (m, 9H), 3.9-4.0 (m, 1H), 5.25 (m, 1H),7.0 (m, 3H), 7.15 (dd, 1H), 7.2 (s, OH), 7.3-7.4 (m, 3H), 7.45-7.55 (m,4H); MS [M-CF3COO]⁺: 454.

EXAMPLE 14

3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 8 mg,19%. ¹H-NMR (DMSO-d6): δ 1.45-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.05(m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 3.0-3.15 (m, 1H), 3.2-3.5 (m, 6H),3.8-3.95 (m, 1H), 5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.13(dd, 1H), 7.2 (s, OH), 7.3-7.4 (m, 4H), 7.45-7.5 (m, 2H), 7.52 (dd, 1H);MS [M-CF3COO]⁺: 468.

EXAMPLE 15

3(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 2. The yield of final step was 7 mg,26%. ¹H-NMR (DMSO-d6): δ 1.6-1.75 (m, 2H), 1.8-2.0 (m, 4H), 2.25 (m,1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m, 6H), 3.8-3.95 (m, 1H),5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.1 (dd, 1H), 7.18 (s,OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H), 7.51 (dd, 1H); MS [M-CF3COO]⁺:468.

EXAMPLE 16

3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 11 mg,26%. ¹H-NMR (DMSO-d6): δ 1.5-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0 (m,2H), 2.25 (m, 1H), 3.15-3.6 (m, 5H), 3.7 (m, 2H), 4.0 (m, 2H), 4.4 (m,2H), 5.25 (m, 1H), 6.95-7.03 (m, 4H), 7.12 (dd, 1H), 7.2 (s, OH),7.3-7.4 (m, 5H), 7.4-7.5 (m, 3H); MS [M-CF3COO]⁺: 464.

EXAMPLE 17

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The yield of final step was 240 mg, 77%.¹H-NMR (DMSO-d6): δ 1.55-2.0 (m, 4H), 2.27 (m, 1H), 3.05-3.55 (m, 5H),3.88-3.98 (m, 1H), 4.0-4.10 (m, 2H), 5.21 (m, 1H), 6.23-6.31 (doble dd,1H), 6.36-6.48 (m, 2H), 6.83-6.90 (dd, 1H), 6.95 (d, OH), 7.26-7.66 (m,11H); MS [M-Br]⁺: 444; mp 99° C.

EXAMPLE 18

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The yield of final step was 210 mg, 66%.¹H-NMR (DMSO-d6): δ 1.50-2.05 (m, 4H), 2.27 (m, 1H), 3.20 (m, 1H),3.37-3.65 (m, 4H), 3.65-3.75 (m, 2H), 4.04 (m, 1H), 4.40 (m, 2H), 5.21(m, 1H), 6.23-6.32 (doble dd, 1H), 6.44 (m, 1H), 6.94-7.04 (m, 4H),7.33-7.50 (m, 7H), 7.64 (m, 1H); MS [M-Br]⁺: 448; mp 163° C.

EXAMPLE 19

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 11 mg,23%. ¹H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.80-2.10 (m, 2H), 2.27 (m,1H), 3.15-3.65 (m, 5H), 3.68 (m, 2H), 4.0 (m, 1H), 4.40 (t, 2H), 5.20(m, 1H), 6.23 (d, 1H), 6.42 (m, 1H), 6.92-7.04 (m, 4H), 7.30-7.38 (m,5H), 7.44-7.50 (m, 2H), 7.64 (m, 1H); MS [M-CF3COO]⁺: 448.

EXAMPLE 20

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound has been described in method-a-.

EXAMPLE 21

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Bromide

The title compound was synthesised according to methods c and a fromintermediate I-1a, diastereomer 1. The yield of final step was 1.15 g99%. ¹H-NMR (DMSO-d6): δ 1.60-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H),3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.25 (dd,1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m, 1H); MS[M-Br]⁺: 462; mp 156° C.

EXAMPLE 22

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 2. The yield of final step was 10 mg,20%. ¹H-NMR (DMSO-d6): δ 1.50-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H),3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.35 (dd,1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m, 1H); MS[M-CF3COO]⁺: 462.

EXAMPLE 23

3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 12 mg, 13%.¹H-NMR (DMSO-d6): δ 1.5 (m, 1H), 1.7 (m, 1H), 1.9-2.05 (m, 2H), 2.3 (m,1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25(m, 1H), 6.3 (d, 1H), 6.45 (m, 1H), 6.95 (d, 1H), 7.25-7.45 (m, 8H), 7.5(m, 2H), 7.7 (m, 1H); MS [M-CF₃COO]⁺: 432.

EXAMPLE 24

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 16 mg,40%. ¹H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.3 (m,1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25(m, 1H), 6.26 (dd, 1H), 6.46 (m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m,8H), 7.5 (m, 2H), 7.7 (m, 1H); MS [M-CF3COO]⁺: 432.

EXAMPLE 25

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 2. The yield of final step was 14 mg,35% ¹H-NMR (DMSO-d6): δ 1.50-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.3 (m,1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25(m, 1H), 6.32 (dd, 1H), 6.46 (m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m,8H), 7.5 (m, 2H), 7.7 (m, 1H) MS [M-CF3COO]⁺: 432.

EXAMPLE 26

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 10 mg,21%. ¹H-NMR (DMSO-d6): δ 1.60-1.75 (m, 2H), 1.80-2.0 (m, 4H), 2.25 (m,1H), 2.50-2.60 (m, 2H), 3.0 (m, 1H), 3.10-3.50 (m, 6H), 3.83 (m, 1H),5.17 (m, 1H), 6.25 (d, 1H), 6.45 (m, 1H), 6.95 (s, 1H), 7.20-7.40 (m,8H), 7.46-7.48 (m, 2H), 7.66 (m, 1H); MS [M-CF3COO]⁺: 446.

EXAMPLE 27

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 9 mg,19%. ¹H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.85-2.05 (m, 2H), 2.30 (m,1H), 3.10-3.40 (m, 3H), 3.40-3.60 (m, 6H), 3.95 (m, 1H), 5.24 (m, 1H),6.27 (d, 1H), 6.47 (m, 1H), 6.96 (s, 1H), 7.0-7.04 (m 2H), 7.36-7.48 (m,4H), 7.49-7.54 (m, 2H), 7.70 (m, 1H).; MS [M-CF3COO]⁺: 438.

EXAMPLE 28

3(R)-[2(*)—(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 9 mg,19%. ¹H-NMR (DMSO-d6): δ 1.60-1.75 (m, 2H), 1.80-2.05 (m, 4H), 2.26 (m,1H), 2.81 (t, 2H), 3.02 (m, 1H), 3.10-3.45 (m, 6H), 3.85 (m, 1H), 5.18(m, 1H), 6.25 (d, 1H), 6.45 (m, 1H), 6.90-7.0 (m, 3H), 7.32-7.42 (m,4H), 7.45-7.51 (m, 2H), 7.66 (m, 1H); MS [M-CF3COO]⁺: 452.

EXAMPLE 29

3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 18 mg, 20%.¹H-NMR (DMSO-d6): δ 1.65-2.05 (m, 4H), 2.3 (m, 1H), 3.0 (m, 2H),3.15-3.6 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 6.35 (dd, 1H), 6.45 (m,1H), 7.05 (m, 1H), 7.2 (dd, 1H), 7.25-7.5 (m, 6H), 7.55 (m, 1H), 7.65(m, 1H); MS [M-CF₃COO]⁺: 438.

EXAMPLE 30

3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 22 mg, 23%.¹H-NMR (DMSO-d6): δ 2.65-2.05 (m, 4H), 2.3 (m, 1H), 3.15-3.65 (m, 7H),4.05 (m, 1H), 4.4 (m, 2H), 5.15 (m, 1H), 6.35 (dd, 1H), 6.45 (m, 1H),6.95-7.05 (m, 4H), 7.15 (d, 1H), 7.3-7.4 (m, 3H), 7.5 (dd, 1H), 7.65 (d,1H); MS [M-CF₃COO]⁺: 454.

EXAMPLE 31

3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 15.4 mg, 15%.¹H-NMR (DMSO-d6): δ 1.65-2.1 (m, 6H), 7.05-7.55 (m, 9H), 3.95 (m, 1H),5.1 (m, 1H), 6.35 (dd, 1H), 6.5 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 7.3(d, 1H), 7.55 (m, 3H), 7.7 (dd, 2H), 8.0 (d, 2H); MS [M-CF₃COO]⁺: 480.

EXAMPLE 32

1-(3-phenoxypropyl)-3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-yl-acetoxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The yield of final step was 100 mg, 41%.¹H-NMR (DMSO-d6): δ 1.65-2.05 (m, 4H), 2.1-2.0 (m, 2H), 2.3 (m, 1H),3.15 (m, 1H), 3.25-3.6 (6H), 3.9-4.1 (m, 3H), 5.1 (m, 1H), 6.35 (d, 1H),6.45 (s, 1H), 6.95 (m, 3H), 7.05 (m, 1H), 7.2 (d, 1H), 7.3 (m, 3H), 7.55(d, 1H), 7.7 (s, 1H); MS [M-Br]⁺: 520; mp 173° C.

EXAMPLE 33

1-(3-phenoxypropyl)-3(R)-(2,2-difuran-2-yl-2-hydroxyacetoxy)-1-azoniabicyclo[2.2.2]octane; Bromide

The title compound was synthesised according to methods f and a. Theyield of final step was 200 mg, 60%. ¹H-NMR (DMSO-d6): δ 1.6-2.20 (m,6H), 2.3 (m, 1H), 2.95-3.65 (m, 7H), 3.80-4.10 (m, 3H), 5.2 (m, 1H),6.3-6.6 (m, 4H), 6.8-7.0 (m, 3H), 7.1 (s, OH), 7.3 (m, 2H), 7.7 (m, 2H);MS [M-Br]⁺: 452.

EXAMPLE 34

3(R)-(2,2-Dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 240 mg, 60%. ¹H-NMR (DMSO-d6): δ 1.85-2.10 (m,4H), 2.30 (s, 1H), 3.40 (m, 1H), 3.44-3.80 (m, 6H), 4.10 (m, 1H), 4.45(m, 2H), 5.20 (m, 1H), 5.90 (s, 1H), 6.95-7.05 (m, 5H), 7.05-7.15 (m,2H), 7.30-7.40 (m, 2H), 7.45 (m, 2H); MS [M-Br]⁺: 454; mp 98° C.

EXAMPLE 35

3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 280 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.80-2.06 (m,4H), 2.06-2.20 (m, 2H), 2.20-2.30 (m, 1H), 3.20-3.65 (m, 7H), 3.90-4.10(m, 3H), 5.20 (m, 1H), 5.90 (s, 1H), 6.95-7.05 (m, 5H), 7.05-7.20 (m,2H), 7.30-7.35 (m, 2H), 7.50 (m, 2H); MS [M-Br]⁺: 468; mp 148° C.

EXAMPLE 36

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 59%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (4H,m), 2.35 (m, 1H), 3.0 (m, 2H), 3.2-3.6 (m, 7H), 3.95 (m, 1H), 5.25 (m,1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.35 (m, 5H), 7.55 (m, 3H); MS [M-Br]⁺:454; mp 216° C.

EXAMPLE 37

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 450 mg, 58%. ¹H-NMR (CDCl3): δ 1.8-2.1 (m, 6H),2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H), 4.2 (m, 1H), 5.25 (m, 1H),6.1 (bs, OH), 6.9 (m, 2H), 7.1-7.3 (m, 9H); MS [M-Br]⁺: 468; mp 64° C.

EXAMPLE 38

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 260 mg, 34%. ¹H-NMR (CDCl3): δ 1.8-2.05 (m, 4H),2.4 (m, 1H), 3.55-3.95 (m, 5H), 4.15-4.5 (m, 3H), 5.25 (m, 1H), 5.9 (s,OH), 6.15 (m, 1H), 6.85 (t, 1H), 6.9-7.05 (m, 3H), 7.15 (m, 1H),7.2-7.45 (m, 7H); MS [M-Br]⁺: 466; mp 124° C.

EXAMPLE 39

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 320 mg, 40%. ¹H-NMR (CDCl3): δ 1.6-2.0 (m, 8H),2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H), 4.2 (m, 1H), 5.25 (m, 1H),6.05 (bs, OH), 6.95 (m, 2H), 7.1-7.3 (m, 9H); MS [M-Br]⁺: 482; mp 64° C.

EXAMPLE 40

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 6H),2.15 (m, 1H), 3.1 (t, 2H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 5.25 (m,1H), 7.0 (d, 2H), 7.15 (d, 2H), 7.55 (m, 5H), 7.65 (t, 1H), 8.0 (d, 2H);MS[M-CF₃COO]⁺: 496.

EXAMPLE 41

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 14%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 5H),2.3 (m, 1H), 3.0-3.5 (m, 9H), 3.9 (m, 1H), 5.25 (m, 1H), 5.65 (t, 1H),6.55 (m, 3H), 7.0 (d, 2H), 7.1 (t, 2H), 7.15 (m, 2H), 7.5 (m, 3H);MS[M-CF₃COO]⁺: 483.

EXAMPLE 42

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 20 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,6H), 2.9 (s, 3H), 3.1 (m, 1H), 3.2-3.45 (m, 8H), 3.95 (m, 1H), 5.2 (m,1H), 6.65 (t, 1H), 6.75 (d, 2H), 7.0 (m, 2H), 7, 2 (m, 4H), 7.5 (m, 3H);MS [M-CF₃COO]⁺: 497.

EXAMPLE 43

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 800 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.6-1.9 (m,6H), 2.3 (m, 1H), 2.95 (t, 2H), 3.05 (m, 1H), 3.2-3.5 (m, 6H), 3.9 (m,1H), 5.2 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.2 (m, 1H), 7.35 (m, 4H),7.5 (m, 2H); MS [M-Br]⁺: 500.

EXAMPLE 44

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 490 mg, 90%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H),1.95 (m, 2H), 2.1 (m, 2H), 2.3 (m, 1H), 3.2 (m, 1H), 3.45 (m, 6H), 4.0(m, 3H), 5.15 (m, 1H), 6.9 (m, 3H), 7.0 (m, 2H), 7.2 (m, 2H), 7.3 (t,2H), 7.5 (m, 3H); MS [M-Br]⁺: 484; mp 227° C.

EXAMPLE 45

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-o-tolyloxypropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b Theyield of final step was 19 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 4H),2.1-2.2 (m, 5H), 2.3 (m, 1H), 3.15-3.5 (m, 7H), 3.9-4.05 (m, 3H), 5.05(m, 1H), 6.85 (t, 1H), 6.9 (d, 1H), 7.0 (m, 2H), 7.15 (m, 4H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 498.

EXAMPLE 46

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H),1.95 (m, 2H), 2.1 (m, 2H), 2.2 (s, 9H), 2.35 (m, 1H), 3.2-3.5 (m, 7H),3.7 (t, 2H), 3.95 (m, 1H), 5.25 (m, 1H), 6.8 (s, 2H), 7.0 (m, 2H), 7.2(m, 2H), 7.5 (m, 3H); MS [M-CF₃COO]⁺: 526.

EXAMPLE 47

1-[3-(2-tert-Butyl-6-methylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.3 (s, 9H), 2.7(m, 2H), 2.9 (m, 2H), 2.1 (m, 2H), 2.2 (s, 3H), 2.3 (m, 1H), 3.2-3.5 (m,7H), 3.8 (t, 2H), 3.95 (m, 1H), 5.2 (m, 1H), 6.9-7.15 (m, 7H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 554.

EXAMPLE 48

1-[3-(Biphenyl-4-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]-octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H), 1.9(m, 2H), 2.15 (m, 2H), 2.3 (m, 1H), 3.2-3.5 (m, 7H), 3.95 (m, 1H), 4.1(t, 2H), 5.25 (m, 1H), 7.0 (m, 4H), 7.2 (m, 2H), 7.3 (t, 1H), 7.45 (t,2H), 7.5 (m, 3H), 7.6 (m, 4H); MS [M-CF₃COO]⁺: 560.

EXAMPLE 49

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 23 mg, 21%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 6H),1.9-2.1 (m, 4H), 2.3 (m, 1H), 2.65 (m, 4H), 3.15-3.5 (m, 7H), 3.95 (m,2H), 5.25 (m, 1H), 6.65 (m, 2H), 6.95 (d, 1H), 7.0 (m, 2H), 7.2 (m, 2H),7.5 (m, 3H); MS [M-CF₃COO]⁺: 538.

EXAMPLE 50

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(naphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 4H),2.1 (m, 1H), 2.35 (m, 1H), 3.15-3.35 (m, 7H), 3.95 (m, 1H), 4.17 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 3H), 7.35 (m, 2H), 7.5 (m, 4H),7.85 (m, 3H); MS [M-CF₃COO]⁺: 534.

EXAMPLE 51

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound has been described in method-b-.

EXAMPLE 52

1-[3-(2-Chlorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 20 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 2H), 7.0 (m, 3H), 7.2 (m, 3H), 7.35 (t, 1H), 7.45 (d, 1H),7.55 (m, 3H); MS [M-CF₃COO]⁺: 519.

EXAMPLE 53

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Chloride

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 59%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.25 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 2H), 4.0 (t,2H), 5.25 (m, 1H), 7.0 (m, 4H), 7.15 (m, 4H), 7.55 (m, 3H); MS [M-Cl]⁺:502; mp 160° C.

EXAMPLE 54

1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.15 (m, 2H), 2.35 (m, 1H), 3.2 (m, 1H), 3.25-3.35 (m, 6H), 3.95(m, 1H), 4.1 (t, 2H), 5.15 (m, 1H),! 7.05 (m, 3H), 7.2 (d, 2H),7.25-7.35 (m, 2H), 7.55 (m, 3H); MS [M-CF₃COO]⁺: 520.

EXAMPLE 55

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.25-7.35 (m, 3H), 7.5-7.6(m, 4H); MS [M-CF₃COO]⁺: 552.

EXAMPLE 56

1-[3-(3-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7, 18 (m, 2H), 7.3 (d, 1H), 7.45 (m,2H), 7.55 (m, 4H); MS [M-CF₃COO]⁺: 509.

EXAMPLE 57

1-[3-(4-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 53%. ¹H-NMR (DMSO-d6): δ 1.65-2.2 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.1 (d, 2H), 7.15 (m, 2H), 7.5 (m, 2H),7.8 (d, 2H); MS [M-Br]⁺: 509; mp 158° C.

EXAMPLE 58

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.15 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.75 (s, 3H), 3.95 (m,1H), 4.0 (t, 2H), 5.25 (m, 1H), 6.55 (m, 3H), 7.0 (m, 2H), 7.2 (m, 3H),7.55 (m, 3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 59

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.7 (s, 3H), 3.9-4.0(m, 3H), 5.25 (m, 1H), 6.9 (s, 4H), 7.0 (m, 2H), 7.15 (m, 2H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 60

1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,7H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.9-4.0 (m, 3H), 5.25(m, 1H), 5.95 (s, 2H), 6.4 (d, 1H), 6.65 (s, 1H), 6.85 (d, 1H), 7.0 (m,2H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF₃COO]⁺: 528.

EXAMPLE 61

1-[3-(2-Carbamoylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%.¹H-NMR (DMSO-d6): δ 1.65-2.0 (m, 4H),2.2 (m, 2H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H),4.15 (t, 2H), 5.25 (m, 1H), 7.0-7.2 (m, 6H), 7.4-7.6 (m, 6H), 7.7 (d,1H); MS [M-CF₃COO]⁺: 527.

EXAMPLE 62

1-[3-(3-Dimethylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.3 (m, 1H), 2.85 (s, 6H), 3.1-3.5 (m, 7H), 3.85-4.0 (m, 3H), 5.25(m, 1H), 6.2 (m, 1H), 6.25 (d, 1H), 6.35 (d, 1H), 7.0 (m, 2H), 7.1 (t,1H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF₃COO]⁺: 527.

EXAMPLE 63

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.2 (m, 2H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3 3.5 (m, 6H), 3.95 (m,1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 4H), 7.5 (m, 3H),8.15 (d, 2H); MS [M-CF₃COO]⁺: 529.

EXAMPLE 64

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-2.2 (m,6H), 2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 4.2 (t, 2H), 5.25 (m,1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.45 (dd, 1H), 7.55 (m, 3H), 7.6 (t, 1H),7.75 (s, 1H), 7.85 (d, 1H); MS [M-CF₃COO]⁺: 529.

EXAMPLE 65

1-[3-(4-Acetylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.0 (s, 3H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.9-4.0(m, 3H), 5.25 (m, 1H), 6.85 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m,5H), 9.8 (s, 1H); MS [M-CF₃COO]⁺: 541.

EXAMPLE 66

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-2.2 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.85 (s, 3H), 3.95 (m,1H), 4.1 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.25 (dd,1H), 7.45-7.6 (m, 6H); MS [M-CF₃COO]⁺: 542.

EXAMPLE 67

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-{3-[4-(3-hydroxypropyl)phenoxy]propyl}-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.6-2.15 (m,8H), 2.3 (m, 1H), 2.55 (t, 2H), 3.2 (m, 1H), 3.25-3.55 (m, 9H), 3.85-4.0(m, 3H), 4.45 (t, OH), 5.25 (m, 1H), 7.85 (d, 2H), 7.0 (m, 2H), 7.1 (d,2H), 7.15 (m, 2H), 7.5 (m, 2H); MS [M-CF₃COO]⁺: 542.

EXAMPLE 68

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.2 (m, 6H),2.35 (m, 1H), 3.1-3.5 (m, 7H), 3.9-4.05 (m, 3H), 4.5 (m, 2H), 5.0 (t,OH), 5.15 (m, 1H), 6.9-7.05 (m, 4H), 7.2 (m, 2H), 7.4 (d, 1H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 69

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.2 (m, 6H),2.35 (m, 1H), 3.15-3.5 (m, 7H), 3.9 (m, 1H), 4.05 (t, 2H), 4.45 (d, 2H),5, 25 (m, 2H), 6.8 (d, 1H), 6.9 (m, 2H), 7.2 (m, 2H), 7.25 (t, 1H), 7.5(m, 3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 70

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-2.2 (m,6H), 2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.9-4.05 (m, 3H), 4.4 (d, 2H), 5.1(t, OH), 5.25 (t, 1H), 6.9 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.25 (d,2H), 7.5 (m, 3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 71

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 24 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 4.0 (t,2H), 5.25 (m, 1H), 6.7-6.85 (m, 3H), 6.95 (d, 1H), 7.0 (m, 2H), 7.2 (m,2H), 7.5 (m, 3H), 8.85 (s, OH); MS [M-CF₃COO]⁺: 500.

EXAMPLE 72

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.25-3.5 (m, 6H), 3.95 (m, 3H), 5.25 (m,1H), 6.7 (d, 2H), 6.75 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (t, 3H),9.0 (s, OH); MS [M-CF₃COO]⁺: 500.

EXAMPLE 73

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.9-4.0 (m, 3H), 5.25(m, 1H), 6.9-6.0 (m, 3H), 7.0-7.1 (m, 3H), 7.2 (m, 2H), 7.5 (m, 3H),9.45 (s, OH); MS [M-CF₃COO]⁺: 500.

EXAMPLE 74

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 21 mg, 22%. ¹H-NMR (DMSO-d6): δ 1.65-1.8 (m,2H), 1.8-2.0 (m, 2H), 2.0-2.15 (m, 2H), 2.3 (m, 1H), 3.05-3.2 (m, 3H),3.2-3.5 (m, 4H), 3.8-3.95 (m, 3H), 5.2 (m, 1H), 6.05 (t, 2H), 6.75 (t,2H), 7.0 (t, 2H), 7.15 (d, 2H), 7.55 (m, 3H);MS [M-CF₃COO]⁺: 457.

EXAMPLE 75

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.7-1.85 (m,2H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (t, 2H), 3.15-3.55 (m, 7H), 3.95(m, 1H), 5.25 (m, 1H), 7.0 (t, 2H), 7.4 (d, 2H), 7.25 (t, 1H), 7.55 (m,3H), 7.95 (d, 1H), 8.05 (d, 1H); MS [M-CF₃COO]⁺: 502.

EXAMPLE 76

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(1-methyl-[1H]-imidazol-2-ylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 26 mg, 25%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H),1.85-2.05 (m, 4H), 2.3 (m, 1H), 3.25-3.5 (m, 7H), 3.6 (s, 3H), 3.9 (m,1H), 4.2 (t, 2H), 5.2 (m, 1H), 7.0 (m, 3H), 7.15 (m, 2H), 7.3 (m, 1H),7.5 (m, 3H); MS [M-CF₃COO]⁺: 504.

EXAMPLE 77

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 430 mg, 54%. ¹H-NMR (DMSO-d6): δ 1.6-1.8 (m,2H), 2.3 (m, 1H), 3.15-3.3 (m, 4H), 3.35-3.55 (m, 5H), 3.95 (m, 1H),5.25 (m, 1H), 7,0 (m, 4H), 7,15 (m, 2H), 7.4-7.5 (m, 4H); MS [M-Br]⁺:460; mp 206° C.

EXAMPLE 78

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 600 mg, 77%. ¹H-NMR (DMSO-d6): δ 1.6-1.8 (m,2H), 1.85-2.1 (m, 4H), 2.3 (m, 1H), 2.8 (t, 2H), 3.1-3.5 (m, 7H), 3.9(m, 1H), 5.2 (m, 1H), 6.9-7.05 (m, 4H), 7.15 (m, 2H), 7.4 (d, 1H), 7.5(m, 3H); MS [M-Br]⁺: 474; mp 138° C.

EXAMPLE 79

1-[3-(Benzothiazol-2-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 23 mg, 21%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (t,2H), 5.2 (m, 1H), 7.0 (t, 2H), 7.15 (m, 2H), 7.25 (m, 1H), 7.45 (m, 5H),7.7 (d, 1H); MS [M-CF₃COO]⁺: 541.

EXAMPLE 80

1-(3-Benzyloxypropyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65 (m, 2H),1.9 (m, 4H), 2.3 (m, 1H), 3.1-3.4 (m, 7H), 3.5 (t, 2H), 3.9 (m, 1H), 3.9(s, 2H), 5.2 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 498.

EXAMPLE 81

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[6-(4-phenylbutoxy)hexyl]-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 560 mg, 60%. ¹H-NMR (CDCl3): δ 1.2-1.75 (m,16H), 1.8-2.1 (m, 4H), 2.4 (m, 1H), 2.6 (t, 2H), 3.3-3.75 (m, 11H), 4.2(m, 1H), 5.3 (m, 1H), 6.0 (bs, OH), 6.95 (m, 2H), 7.15-7.3 (m, 9H); MS[M-Br]⁺: 582.

EXAMPLE 82

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 240 mg, 30%. ¹H-NMR (DMSO-d6/CDCl3): δ 1.8-1.95(m, 6H), 2.1 (m, 2H), 2.45 (m, 1H), 3.18 (m, 1H), 3.5-3.8 (m, 6H), 4.0(t, 2H), 4.15 (m, 1H) 5.15 (m, 1H), 6.7 (s, OH), 6.9 (m, 5H), 7.15 (d,1H), 7.25 (m, 5H); MS [M-Br]⁺: 498; mp 161° C.

EXAMPLE 83

3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 380 mg, 50%. ¹H-NMR (DMSO-d6): δ 1-85 (m, 2H),2.05 (m, 2H), 2.4 (m, 1H), 3.6-4.1 (m, 7H), 4.35 (m, 3H), 5.25 (m, 1H),6.0 (bs, OH), 6.9 (m, 4H), 7.0 (t, 1H), 7.1 (dd, 2H), 7.2 (dd, 2H), 7.3(t, 2H); MS [M-Br]⁺: 470; mp 48° C.

EXAMPLE 84

1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.3 (m, 1H), 3.2-3.55 (m, 7H), 3.85 (m, 2H), 4.5 (s, 2H), 5.25 (m,1H), 7.0 (t, 2H), 7.15 (t, 2H), 7.3-7.4 (m, 4H), 7.5 (m, 3H); MS[M-CF₃COO]⁺: 484.

EXAMPLE 85

3(S)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 600 mg, 54%. ¹H-NMR (DMSO-d6/CDCl3): δ 1.85-2.3(m, 6H), 2.5 (m, 1H), 3.3 (m, 1H), 3.4 (d, 1H), 3.5-3.7 (m, 5H), 4.05(t, 2H), 4.2 (m, 1H), 5.25 (m, 1H), 6.85 (d, 2H), 7.0 (m, 3H), 7.15 (m,2H), 7.2 (d, 1H), 7.3 (m, 4H); MS [M-Br]⁺: 484; mp 230° C.

EXAMPLE 86

4-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods f and a. Theyield of final step was 290 mg, 60%. ¹H-NMR (DMSO-d6): δ 2.15 (m, 2H),2.35 (m, 6H), 3.35 (m, 2H), 3.65 (m, 6H), 4.05 (t, 2H), 6.9-7.05 (m,5H), 7.1 (m, 2H), 7.3 (m, 3H), 7.55 (m, 2H); MS [M-Br]⁺: 484; mp 1681C.

EXAMPLE 87

4-(2-Hydroxy-2,2-dithien-2-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods f and a. Theyield of final step was 260 mg, 57%. ¹H-NMR (DMSO-d6): δ 2.35 (m, 6H),3.0 (m, 2H), 3.4 (m, 2H), 3.75 (m, 6H), 7.0 (m, 2H), 7.3-7.5 (m, 6H),7.55 (m, 2H); MS [M-Br]⁺: 454; mp 1951C.

EXAMPLE 88

1-(3-phenoxypropyl)-3(R)-(2,2-dithien-2-ylpropionyloxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 390 mg, 92%. ¹H-NMR (DMSO-d6): δ 1.65-2.20 (m,6H), 2.10 (s, 3H), 2.30 (bs, 1H), 3.10 (m, 1H), 3.30-3.60 (m, 6H),3.95-4.10 (m, 3H), 5.20 (m, 1H), 6.90-7.05 (m, 5H), 7.05-7.10 (m, 2H),7.25-7.35 (m, 2H), 7.50 (m, 2H); MS [M-Br]⁺: 482; mp 170° C.

EXAMPLE 89

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 300 mg, 76%. ¹H-NMR (DMSO-d6): δ 1.6 (m, 1H),1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.2 (m, 2H), 2.3 (m, 1H), 3.15 (m,1H), 3.3-3.6 (m, 6H), 3.9 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 6.75 (s,OH), 6.95 (m, 3H), 7.15 (m, 2H), 7.3 (t, 2H), 7.4-7.5 (m, 4H); MS[M-Br]⁺: 484; mp 2191C.

EXAMPLE 90

3(R)-(2-Hydroxy-2,2-dithienyl-3-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 300 mg, 77%. ¹H-NMR (DMSO-d6): δ 1.5-1.6 (m,1H), 1.6-1.75 (m, 1H), 1.8-2.1 (m, 4H), 2.25 (m, 1H), 2.8 (t, 2H),3.05-3.5 (m, 7H), 3.8-3.95 (m, 1H), 5,15 (m, 1H), 6.75 (s, OH), 6.9-7.0(m, 2H), 7.1 (m, 2H), 7.35-7.55 (m, 5H); MS [M-Br]⁺: 474; mp 1921C.

EXAMPLE 91

3(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 63 mg, 48%. ¹H-NMR (DMSO-d6): δ 1.5-1.7 (m, 1H),1.7-1.85 (m, 1H), 1.9-2.1 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H),3.15-3.6 (m, 7H), 3.9-4.0 (m, 1H), 5.2 (m, 1H), 6.8 (s, OH), 7.1 (m,2H), 7.25-7,35 (m, 5H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]⁺: 454.

EXAMPLE 92

3(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 75 mg, 55%. ¹H-NMR (DMSO-d6): δ 1.5-2.0 (m, 6H),2.25 (m, 1H), 2.5-2.6 (m, 2H), 3.05-3.6 (m, 8H), 3.8-3.9 (m, 1H), 5.15(m, 1H), 6.75 (s, OH), 7.1 (d, 2H), 7.2-7,35 (m, 5H), 7.4 (m, 2H), 7.5(m, 2H); MS [M-CF3COO]⁺: 468.

EXAMPLE 93

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 68 mg, 48%. ¹H-NMR (DMSO-d6): δ 1.5-1.8 (m, 6H),1.8-2.0 (m, 2H), 2.25 (m, 1H), 2.6 (m, 2H), 3.05 (m, 1H), 3.15-3.45 (m,6H), 3.85 (m, 1H), 5.15 (m, 1H), 6.75 (s, OH), 7.1 (d, 2H), 7.2 (m, 2H),7,3 (m, 3H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]⁺: 482.

EXAMPLE 94

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 65 mg, 49%. ¹H-NMR (DMSO-d6): δ 1.5-1.65 (m,1H), 1.65-1.78 (m, 1H), 1.85-2.05 (m, 2H), 2.3 (m, 1H), 3.1-3.6 (m, 9H),3.95 (m, 1H), 5,2 (m, 1H), 6.75 (s, OH), 7.0 (m, 2H), 7.15 (m, 2H), 7.45(m, 3H), 7,5 (m, 2H); MS [M-CF3COO]⁺: 460.

EXAMPLE 95

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 63 mg, 43%. ¹H-NMR (DMSO-d6): δ 1.5-2.0 (m, 8H),2.3 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (m, 2H),5.2 (m, 1H), 6.75 (s, OH), 6.95 (m, 3H), 7.1 (d, 2H), 7.2 (m, 2H), 7,3(t, 2H), 7.45 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]⁺: 498.

EXAMPLE 96

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 72 mg, 52%. ¹H-NMR (DMSO-d6): δ 1.55-1.65 (m,1H), 1.7-1.8 (m, 1H), 1.85-2.05 (m, 2H), 2.3 (m, 1H), 3.2-3.6 (m, 5H),3.7 (m, 2H), 4.05 (m, 1H), 4.4 (m, 2H), 5.2 (m, 1H), 6.75 (s, OH),6.95-7.05 (m, 3H), 7.1 (d, 2H), 7.3-7.5 (m, 6H); MS [M-CF3COO]⁺: 470.

EXAMPLE 97

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-3-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 79 mg, 54%. ¹H-NMR (DMSO-d6): δ 1.55-1.65 (m,1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H), 2.05-2.2 (m, 2H), 2.3 (m, 1H),3.1-3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.85-3.95 (m, 1H), 4.0 (t, 2H), 5.2(m, 1H), 6.75 (s, OH), 6.95 (m, 2H), 7.15 (m, 4H), 7.4 (m, 2H), 7.5 (m,2H); MS [M-CF3COO]⁺: 502.

EXAMPLE 98

3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 24 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.8-2.05 (m,4H), 2.3 (m, 1H), 3.15 (m, 1H), 3.3-3.5 (m, 4H), 3.9 (m, 1H), 4.05 (m2H), 5.25 (m, 1H), 6.35 (m, 1H), 6.75 (s, OH), 6.85 (t, 1H), 7.1 (m,2H), 7.3-7.5 (m, 5H), 7.55 (m, 4H); MS [M-CF3COO]⁺: 502.

EXAMPLE 99

1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 400 mg, 93%. ¹H-NMR (DMSO-d6): δ 1.35-1.50 (m,1H), 1.60-1.75 (m, 1H), 1.75-1.95 (m, 2H), 2.10 (m, 1H), 2.85 (m, 1H),3.10 (d, 1H), 3.20-3.50 (m, 3H), 3.85 (m,1H), 4.0 (dd, 2H), 5.05 (m,1H), 6.40 (dd, 1H), 6.80-6.90 (d, 1H), 6.85 (s, OH), 7.20-7.50 (m, 7H),7.60 (m, 4H), 7.80 (m, 2H); MS [M-Br]⁺: 452; mp 146° C.

EXAMPLE 100

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 690 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.47 (m, 1H),1.68 (m, 1H), 1.87 (m, 2H), 2.1 (m, 3H), 2.89 (m, 1H), 3.15 (d, 1H), 3.4(m, 5H), 3.9 (m, 1H), 4.0 (m, 2H), 5.04 (m, 1H), 6.85 (s, OH), 6.97 (m,3H), 7.35 (m, 4H), 7.45 (m, 2H), 7.65 (m, 2H), 7.85 (m, 2H); MS [M-Br]⁺:470; mp 108° C.

EXAMPLE 101

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 170 mg, 74%. ¹H-NMR (DMSO-d6): δ 1.45 (m, 1H),1.65 (m, 1H), 1.85 (m, 2H), 2.1 (m, 1H), 2.9 (m, 3H), 3.15 (m, 1H),3.3-3.5 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 6.85 (s, OH), 7.2-7.4 (m,7H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS [M-Br]⁺:440; mp 118° C.

EXAMPLE 102

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 460 mg, 96%. ¹H-NMR (DMSO-d6): δ 1.42 (m, 1H),1.66 (m, 1H), 1.80-1.88 (m, 2H), 2.08 (m, 1H), 2.93 (m, 1H), 3.25-3.60(m, 4H), 3.65 (m, 2H), 3.95 (m, 1H), 4.35 (m 2H), 5.02 (m, 1H), 6.85 (s,1H, OH), 6.97 (d, 2H), 7.04 (t, 1H), 7.20-7.45 (m, 6H), 7.55-7.60 (t,2H), 7.80 (d, 2H); MS [M-Br]⁺: 456; mp 140° C.

EXAMPLE 103

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 15 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.45 (m, 1H),1.65 (m, 1H), 1.7-2.0 (m, 4H), 2.1 (m, 1H), 2.75 (m, 1H), 3.0-3.2 (m4H), 3.25-3.4 (m, 4H), 3.85 (m, 1H), 5.05 (m, 1H), 6.85 (s, OH), 7.35(t, 2H), 7.45 (t, 2H), 7.55-7.7 (m, 5H), 7.85 (d, 2H), 8.0 (d, 2H); MS[M-CF₃COO]⁺: 482.

EXAMPLE 104

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Chloride

The title compound was synthesised according to methods c and a. Theyield of final step was 440 mg, 94%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 2H), 1.7-1.95 (m, 2H), 2.0-2.1 (m, 3H), 2.8 (m, 1H), 3.1 (d,1H), 3.2-3.4 (m, 5H), 3.8 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 6.85 (s,OH), 6.95 (m, 2H), 7.15 (t, 2H), 7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d,1H), 7.65 (d, 1H), 7.85 (d, 2H); MS [M-Br]⁺: 488; mp 142° C.

EXAMPLE 105

1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.6-1.9 (m, 3H), 2.1 (m, 3H), 2.8 (m, 1H), 3.1 (d, 1H), 3.2-3.4 (m, 5H),3.85 (m, 1H), 4.05 (t, 2H), 5.0 (m, 1H), 6.85 (s, OH), 7.05 (t, 1H),7.15-7.4 (m, 4H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d,2H); MS [M-CF₃COO]⁺: 506.

EXAMPLE 106

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.6(m, 1H), 1.8 (m, 4H), 2.05 (m, 1H), 2.7 (m, 1H), 3, 0 (m, 3H), 3.2-3.4(m, 6H), 3.8 (m, 1H), 5.0 (m, 1H), 5.6 (t, NH), 6.55 (m, 3H), 6.85 (s,OH), 7.1 (t, 2H), 7.35 (dd, 2H), 7.45 (dd, 2H), 7.55 (dd, 2H), 7.8 (d,2H); MS [M-CF₃COO]⁺: 469.

EXAMPLE 107

3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-[3-(4-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 15 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.6(m, 1H), 1.7-1.9 (m, 2H), 1.95-2.05 (m, 2H), 2.1 (m, 1H), 2.8 (m, 1H),3.1 (d, 1H) 3.25-3.4 (m, 5H), 3.8-3.9 (m, 3H), 5.0 (m, 1H), 6.7 (d, 2H),6.75 (d, 2H), 6.85 (s, OH), 7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d, 1H),7.65 (d, 1H), 7.85 (d, 2H), 9.0 (s, OH); MS [M-CF₃COO]⁺: 486.

EXAMPLE 108

1-(2-Benzyloxyethyl)-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 470 mg, 96%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.7-1.9 (m, 2H), 2.1 (m, 1H), 2.9 (m, 1H), 3.15-3.5 (m,6H), 3.75 (m, 2H), 3.85 (m, 1H), 4.5 (s, 2H), 5.0 (m, 1H), 6.85 (s, OH),7.3-7.5 (m, 9H), 7.55 (m, 2H), 7.8 (d, 2H); MS [M-Br]⁺: 470; mp 86° C.

EXAMPLE 109

3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thienyl-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 70%. ¹H-NMR (DMSO-d6): δ 1.37 (m, 1H),1.62 (m, 1H), 1.75-1.95 (m, 4H), 2.06 (m, 1H), 2.72 (m, 1H), 2.80 (m,2H), 3.02-3.06 (m, 1H), 3.15-3.20 (m, 2H), 3.25-3.40 (m, 3H), 3.80 (m,1H), 5.0 (m, 1H), 6.85 (s, 1H, OH), 6.95-7.0 (m, 2H), 7.25-7.50 (m, 5H),7.55-7.65 (m, 2H), 7.85 (d, 2H); MS [M-Br]⁺: 460; mp 140° C.

EXAMPLE 110

3(R)—(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 80 mg, 40%. ¹H-NMR (DMSO-d6): δ 1.35 (m, 1H),1.6 (m, 1H), 1.7-1.90 (m, 2H), 2.05 (m, 1H), 2.5 (m, 2H), 2.7 (m, 1H),3.0 (m, 1H), 3.15 (m, 2H), 3.2-3.4 (m, 3H), 3.75 (m, 1H), 5.0 (m, 1H),6.85 (s, OH), 7.20-7.50 (m, 9H), 7.55 (dd, 2H), 7.85 (d, 2H); MS[M-CF3COO]⁺: 454.

EXAMPLE 111

3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 74 mg, 35%. ¹H-NMR (DMSO-d6): δ 1.35 (m, 1H),1.45-1.65 (m, 5H), 1.7-1.90 (m, 2H), 2.05 (m, 1H), 2.55-2.75 (m, 3H),3.0 (m, 1H), 3.15-3.45 (m, 5H), 3.75 (m, 1H), 5.0 (m, 1H), 6.85 (s, OH),7.20 (m, 3H), 7.25-7.35 (m, 4H), 7.45-7.5 (m, 2H), 7.55-7.6 (dd, 2H),7.85 (d, 2H); MS [M-CF3COO]⁺: 468.

EXAMPLE 112

3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy-1-(2-thienyl-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 79 mg, 39%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.8-1.95 (m, 2H), 2.1 (m, 1H), 2.9 (m, 1H), 3.1-3.25 (m,4H), 3.15-3.45 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 6.85 (s, OH), 7.0(m, 2H), 7.35 (t, 2H), 7.45-7.5 (m, 3H), 7.55 (d, 1H), 7.65 (d, 1H),7.85 (d, 2H); MS[M-CF3COO]⁺: 446.

EXAMPLE 113

3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 72 mg, 33%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.55-1.9 (m, 7H), 2.05 (m, 1H), 2.7 (m, 1H), 3.0 (m, 1H), 3.15-3.5 (m,7H), 3.8 (m, 1H), 4.0 (m, 2H), 5.05 (m, 1H), 6.85 (s, OH), 6.95 (m, 3H),7.25-7.35 (m, 4H), 7.4-7.45 (m, 2H), 7.6 (dd, 2H), 7.85 (d, 2H); MS[M-CF3COO]⁺: 484.

EXAMPLE 114

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 200 mg, 76%. ¹H-NMR (DMSO-d6): δ 1.54 (m, 1H),1.70-1.86 (m, 3H), 1.76 (s, 3H), 2.13 (m, 1H), 3.06 (m, 1H), 3.20-3.50(m, 4H), 3.86 (m, 1H), 4.05 (dd, 2H), 5.02 (m, 1H), 6.43 (dd, 1H), 6.86(d, 1H), 7.26-7.46 (m, 7H), 7.58-7.65 (m, 3H), 7.70-7.72 (m, 1H),7.87-7.90 (m, 2H); MS [M-Br]⁺: 450; mp 234° C.

EXAMPLE 115

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 210 mg, 66%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.60-2.0 (m, 3H), 1.76 (s, 3H), 2.12 (m, 1H), 3.10-3.25 (m, 1H),3.40-3.80 (m, 6H), 4.0 (m, 1H), 4.41 (m, 2H), 4.98 (m, 1H), 6.98-7.05(m, 3H), 7.27-7.46 (m, 6H), 7.63-7.71 (m, 2H), 7.87-7.90 (m, 2H); MS[M-Br]⁺: 454; mp 202° C.

EXAMPLE 116

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 210 mg, 61%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.60-2.0 (m, 3H), 1.78 (s, 3H), 2.0-2.20 (m, 3H), 3.0-3.10 (m, 1H),3.25-3.53 (m, 6H), 3.86 (m, 1H), 4.03 (m, 2H), 4.98 (m, 1H), 6.95-7.0(m, 3H), 7.30-7.48 (m, 6H), 7.65-7.92 m, 4H); MS [M-Br]⁺: 468; mp 204°C.

EXAMPLE 117

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.15 (m, 1H), 2.9-3.1 (m, 4H),3.25-3.55 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 7.25-7.55 (m, 9H), 7.65(d, 1H), 7.75 (d, 1H), 7.95 (d, 2H); MS [M-CF₃COO]⁺: 438.

EXAMPLE 118

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-2.05 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H) 3.0 (m, 1H), 3.1-3.5 (m,8H), 3.85 (m, 1H), 7.35-7.5 (m, 4H), 7.55 (t, 2H), 7.65 (t, 2H), 7.7 (d,1H), 7.9 (d, 2H), 8.0 (d, 2H); MS [M-CF₃COO]⁺: 480.

EXAMPLE 119

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 23 mg, 23%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.15 (m, 3H), 3.0 (m, 1H),3.25-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 6.95 (m, 2H),7.15 (t, 2H), 7.35-7.5 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H);MS [M-CF₃COO]⁺: 486.

EXAMPLE 120

1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9H-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 20 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.2 (m, 3H), 3.0 (m, 1H),3.25-3.55 (m, 6H), 3.85 (m, 1H), 4.1 (t, 2H), 5.0 (m, 1H), 7.05 (t, 1H),7.2-7.5 (m, 6H), 7.65 (d, 1H), 7.75/d, 1H), 7.9 (d, 2H); MS [M-CF₃COO]⁺:504.

EXAMPLE 121

3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H), 2.95 (m, 1H), 3.05 (m,2H), 3.15-3.45 (m, 6H), 3.8 (m, 1H), 5.0 (m, 1H), 5.65 (t, NH), 6.6 (m,3H), 7.1 (t, 2H), 7.35-7.55 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d,2H); MS [M-CF₃COO]⁺: 467.

EXAMPLE 122

1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 22%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.9 (m, 3H), 1.75 (s, 3H), 2.0-2.15 (m, 3H), 3.0 (m, 1H), 3.25-3.5(m, 6H), 3.8-3.95 (m, 3H), 5.0 (m, 1H), 6.7 (d, 1H), 6.75 (d, 1H),7.35-7.45 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H), 9.0 (s, OH);MS [M-CF₃COO]⁺: 484.

EXAMPLE 123

1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 4H), 1.75 (s, 3H), 2.15 (m, 1H), 3.1 (m, 1H), 3.3-3.55 (m,6H), 3.8-3.95 (m, 3H), 4.5 (s, 2H), 5.0 (m, 1H), 7.3-7.5 (m, 9H),7.6-7.7 (m, 2H), 7.9 (d, 2H); MS [M-CF₃COO]⁺: 468.

EXAMPLE 124

3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 420 mg, 89%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 2.15 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.60(m, 6H), 3.85 (m, 1H), 3.95-4.15 (dd, 2H, J1=1.8 Hz, J2=4.2 Hz), 5.02(m, 1H), 5.25 (s, 1H), 7.25-7.43 (m, 11H), 7.48-7.55 (m, 2H); MS[M-Br]⁺: 438; mp 216° C.

EXAMPLE 125

3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 450 mg, 82%. ¹H-NMR (DMSO-d6): δ 1.56 (m, 1H),1.65-1.95 (m, 3H), 2.05-2.15 (m, 3H), 3.10 (m, 1H), 3.20-3.50 (m, 6H),3.80 (m, 1H), 3.94-4.14 (m, 4H), 5.0 (m, 1H), 5.22 (s, 1H), 6.94-7.0 (m,3H), 7.25-7.35 (m, 6H), 7.40 (m, 2H), 7.54-7.47 (m, 2H); MS [M-Br]⁺:468; mp 157° C.

EXAMPLE 126

1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 83 mg, 21%. ¹H-NMR (DMSO-d6): δ 1.50-2.0 (m,8H), 2.15 (m, 1H), 2.65 (m, 2H), 3.05-3.65 (m, 7H), 3.80 (m, 1H), 5.0(m, 1H), 5.30 (s, 1H), 7.10-7.45 (m, 11H), 7.45-7.60 (m, 2H); MS[M-Br]⁺: 468; mp 95° C.

EXAMPLE 127

1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 300 mg, 73%. ¹H-NMR (DMSO-d6): δ 1.70-2.0 (m,4H), 2.2 (m, 1H), 3.20-3.80 (m, 7H), 4.0 (m, 1H), 4.40 (m, 2H), 5.05 (m,1H), 5.30 (s, 1H), 7.0-7.10 (m, 7H), 7.30-7.45 (m, 4H), 7.45-7.55 (m,2H); MS [M-Br]⁺: 456; mp 200° C.

EXAMPLE 128

1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 350 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.70-2.0 (m,4H), 2.0-2.25 (m, 3H), 3.15-3.65 (m, 7H), 3.85-3.95 (m, 1H), 3.95-4.10(m, 2H), 5.0 (m, 1H), 5.30 (s, 1H), 6.90-7.0 (m, 3H), 7.10-7.25 (m, 4H),7.25-7.40 (m, 4H), 7.40-7.60 (m, 2H); MS [M-Br]⁺: 470; mp 184° C.

EXAMPLE 129

1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 100 mg, 44%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.1 (m, 1H), 2.9-3.05 (m, 2H), 3.15-3.6 (m, 7H), 3.85 (m, 1H), 5.05(m, 1H), 5.3 (s, 1H)), 7.15-7.55 (m, 13H); MS [M-Br]⁺: 440.

EXAMPLE 130

1-(4-Oxo-4-phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65-2.05 (m,6H), 2.1 (m, 1H), 3.1-3.55 (m, 9H), 3.8 (m, 1H), 5.05 (m, 1H), 5.25 (s,1H), 7.1-7.3 (m, 4H), 7.35 (t, 2H), 7.45-7.6 (m, 4H), 7.7 (d, 1H), 8.0(d, 1H); MS [M-CF₃COO]⁺: 482.

EXAMPLE 131

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane,Trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 18 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.7-2.1 (m, 6H),2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.8 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H),5.3 (s, 1H), 6.95 (m, 2H), 7.1-7.3 (m, 6H), 7.4 (t, 2H), 7.5 (dd, 2H);MS [M-CF₃COO]⁺: 488.

EXAMPLE 132

1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 14 mg, 14%. ¹H-NMR (DMSO-d6): δ 1.65-1.95 (m,4H), 2.05-2.2 (m, 3H), 3.1-3.55 (m, 7H), 3.8 (m, 1H), 4.05 (t, 2H), 5.0(m, 1H), 5.3 (s, 1H), 7.05 (t, 1H), 7.1-7.55 (m, 10H); MS [M-CF₃COO]⁺:506.

EXAMPLE 133

1-(3-Phenylaminopropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 17 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,6H), 2.15 (m, 1H), 3.0-3.5 (m, 9H), 1.75 (m, 1H), 5.0 (m, 1H), 5.3 (s,1H), 6.65 (t, NH), 6.55 (m, 3H), 0.05-7.3 (m, 6H), 7.35-7.55 (m, 4H); MS[M-CF₃COO]⁺: 469.

EXAMPLE 134

1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 21 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.7-2.1 (m, 6H),2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.7-3.95 (m, 3H), 5.0 (m, 1H), 5.3 (s,1H), 6.7 (d, 2H), 6.75 (d, 2H), 7.1-7.3 (m, 4H), 7.35-7.55 (m, 4H), 9.0(s, OH); MS [M-CF₃COO]⁺: 486.

EXAMPLE 135

1-(2-Benzyloxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 16 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-1.95 (m,4H), 2.1 (m, 1H), 3.1-3.9 (m, 10H), 4.5 (s, 2H), 5.0 (m, 1H), 5.3 (s,1H), 7.15 (m, 4H), 7.3-7.5 (m, 7H), 7.55 (t, 2H); MS [M-CF₃COO]⁺: 470.

EXAMPLE 136

3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 340 mg, 71%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 1.95-2.10 (m, 3H), 2.70 (m, 1H), 2.90(m, 1H), 3.2-3.5 (m, 5H), 3.80 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H),6.90-7.0 (m, 3H), 7.20-7.35 (m, 7H), 7.40-7.46 (m, 2H), 7.65-7.70 (m,2H); MS [M-Br]⁺: 486; mp 219° C.

EXAMPLE 137

3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 290 mg, 64%. ¹H-NMR (DMSO-d6): δ 1.32 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.1 (m, 1H), 2.75-2.90 (m, 3H), 3.05(m, 1H), 3.30-3.50 (m, 5H), 3.82 (m, 1H), 5.05 (m, 1H), 7.20-7.40 (m,10H), 7.40-7.50 (m, 2H), 7.65-7.70 (m, 2H); MS [M-Br]⁺: 456; mp 221° C.

EXAMPLE 138

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 310 mg, 97%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.62 (m, 1H), 1.70-1.90 (m, 4H), 2.05 (m, 1H), 2.60 (m, 1H), 2.75-2.85(m, 4H), 3.15 (m, 2H), 3.25-3.40 (m, 2H), 3.75 (m, 1H), 5.0 (m, 1H),6.93 (m, 1H), 7.0 (m, 1H), 7.14-7.26 (m, 5H), 7.36-7.45 (m, 3H),7.63-7.67 (m, 2H); MS [M-Br]⁺: 476; mp 111° C.

EXAMPLE 139

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 85 mg, 41%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.05 (m, 1H), 2.5-2.6 (m, 2H), 2.80 (m,1H), 3.05-3.75 (m, 7H), 5.05 (m, 1H), 7.1-7.45 (m, 12H), 7.65-7.70 (m,2H); MS [M-CF3COO]⁺: 470.

EXAMPLE 140

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 84 mg, 38%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.4-1.85 (m, 7H), 2.05 (m, 1H), 2.5-2.6 (m, 2H), 2.80 (m, 1H), 3.05-3.4(m, 6H), 3.7 (m, 1H), 5.05 (m, 1H), 7.15-7.35 (m, 10H), 7.4 (m, 1H),7.65 (m, 2H); MS [M-CF3COO]⁺: 484.

EXAMPLE 141

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 81 mg, 39%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.6 (m, 1H), 1.7-1.9 (m, 2H), 2.05 (m, 1H), 2.75 (m, 1H), 3.0 (m, 1H),3.1-3.2 (m, 2H), 3.3-3.6 (m, 5H), 3.8 (m, 1H), 5.05 (m, 1H), 6.95-7.0(m, 2H), 7.15-7.3 (m, 5H), 7.45 (m, 3H), 7.65 (m, 2H); MS [M-CF3COO]⁺:462.

EXAMPLE 142

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 83 mg, 37%. ¹H-NMR (DMSO-d6): δ 1.3 (m, 1H),1.5-1.9 (m, 7H), 2.05 (m, 1H), 2.6 (m, 1H), 2,8 (m, 1H), 3.1-3.45 (m,7H), 3.75 (m, 1H), 4.0 (m, 2H), 5.05 (m, 1H), 6.95-7.0 (m, 3H),7.15-7.45 (m, 9H), 7.65 (m, 2H); MS [M-CF3COO]⁺: 500.

EXAMPLE 143

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 102 mg, 48%. ¹H-NMR (DMSO-d6): δ 1.3 (m, 1H),1.55-1.95 (m, 3H), 2.05 (m, 1H), 2,8 (m, 1H), 3.1 (m, 1H), 3.35-3.65 (m,5H), 3.9 (m, 1H), 4.35 (m, 2H), 5.05 (m, 1H), 6.95 (d, 2H), 7.0-7.1 (m,2H), 7.2 (m, 4H), 7.3-7.45 (m, 4H), 7.6 (t, 2H); MS [M-CF3COO]⁺: 472.

EXEMPLE 144

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 99 mg, 44%. ¹H-NMR (DMSO-d6): δ 1.3 (m, 1H), 1.6(m, 1H), 1.7-2.0 (m, 4H), 2.05 (m, 1H), 2.7 (m, 1H), 2.9 (m, 1H),3.2-3.5 (m, 5H), 3.75-3.85 (m, 1H), 3.95 (m, 2H), 5.0 (m, 1H), 6.95 (m,2H), 7.1-7.3 (m, 7H), 7.45 (t, 2H), 7.65 (t, 2H); MS [M-CF3COO]⁺: 504.

EXEMPLE 145

3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 25 mg, 12%. ¹H-NMR (DMSO-d6): δ 1.25-1.30 (m,1H), 1.55-1.95 (m, 3H), 2.10 (m, 1H), 2.65-2.75 (m, 1H), 2.9 (m, 1H),3.25-3.50 (m, 2H), 3.75-3.8 (m,1H), 3.95 (m, 2H), 4.2 (d, 1H), 5.0 (m,1H), 6.35 (m, 1H), 6.80 (d, 1H), 7.05-7.50 (m, 8H), 7.60 (m, 4H); MS[M-CF3COO]⁺: 468.

EXAMPLE 146

3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 110 mg. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65(m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.05-2.15 (m, 3H), 1.8 (m, 1H),3.15 (m, 2H), 3.25-3.5 (m, 5H), 3.85 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H),6.95-7.0 (m, 3H), 7.15-7.2 (m, 4H), 7.3-7.4 (m, 4H), 7.45 (d, 1H), 7.55(d, 1H); MS [M-Br]⁺: 484; mp 195° C.

EXAMPLE 147

3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H), 2.15 (m, 1H), 2.8-2.95 (m,3H), 3.15 (d, 1H), 3.3-3.5 (m, 5H), 4.9 (m, 1H), 5.1 (m, 1H), 7.15 (m,4H), 7.25-7.4 (m, 7H), 7.45 (d, 1H), 7.55 (d, 1H); MS [M-CF₃COO]⁺: 454.

EXAMPLE 148

3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 24 mg, 24%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H), 2.15 (m, 1H), 2.95 (m, 1H),3.25 (m, 1H), 3.4-3.65 (m, 5H), 3.85 (m, 1H), 4.35 (t, 2H), 5.05 (m,1H), 6.95 (d, 2H), 7.05 (t, 2H), 7.15 (m, 3H), 7.25-7.45 (m, 6H); MS[M-CF₃COO]⁺: 470.

EXAMPLE 149

3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 7H), 2.15 (m, 1H), 2.8 (m, 1H), 3.05-3.25(m, 4H), 3.3-3.5 (m, 4H), 3.85 (m, 1H), 5.05 (m, 1H), 7.15 (m, 4H), 7.35(t, 2H), 7.45-7.6 (m, 4H), 7.7 (t, 1H), 8.0 (d, 2H); MS [M-CF₃COO]⁺:496.

EXAMPLE 150

1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 25 mg, 24%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 1-95-2.1 (m, 2H), 2.15 (m,1H), 2.8 (m, 1H), 3.1 (d, 1H), 3.25-3.5 (m, 5H), 3.8 (m, 1H), 4.0 (t,2H), 5.05 (m, 1H), 6.95 (m, 2H), 7.15 (m, 6H), 7.35 (t, 2H), 7.5 (dd,2H); MS [M-CF₃COO]⁺: 502.

EXAMPLE 151

1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.0-2.15 (m, 3H), 2.8 (m,1H), 3.1 (d, 1H), 7.05 (t, 1H), 7.1-7.4 (m, 8H), 7.5 (dd, 2H); MS[M-CF₃COO]⁺: 520.

EXAMPLE 152

3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.35 (m, 1H),1.6 (m, 1H), 1.7-1.9 (m, 4H), 1.9 (s, 3H), 2.1 (m, 1H), 2.7 (m, 1H),2.95-3.05 (m, 3H), 3.1-3.4 (m, 6H), 3.75 (m, 1H), 5.0 (m, 1H), 5.6 (m,1H), 6.55 (m, 3H), 7.05-7.15 (m, 6H), 7.3 (m, 2H), 7.45 (t, 2H); MS[M-CF₃COO]⁺: 483.

EXAMPLE 153

1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 2.75-2.05 (m, 4H), 1.9 (s, 3H), 2.15 (m, 1H), 2.8 (m, 1H),3.1 (d, 1H), 3.25-3.5 (m, 5H), 3.8-3.95 (m, 3H), 5.05 (m, 1H), 6.65-6.8(m, 4H), 7.2 (m, 4H), 7.35 (t, 2H), 7.5 (m, 2H), 9.0 (s, OH); MS[M-CF₃COO]⁺: 500.

EXAMPLE 154

1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 14%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.1 (m, 1H), 2.9 (m, 1H),3.2-3.5 (m, 6H), 3.75-3.95 (m, 3H), 4.5 (s, 2H), 5.05 (m, 1H), 7.15 (m,4H), 7.3-7.5 (m, 9H); MS [M-CF₃COO]⁺: 484.

EXAMPLE 155

1-(3-Phenoxypropyl)-3(R)-(9[H]-thioxanthene-9-carbonyloxy)-1-azonia-bicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 323 mg, 50%. ¹H-NMR (DMSO-d6): δ 1.35 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.0-2.2 (m, 3H), 2.75-2.90 (m, 1H),3,12 (m, 1H), 3.25-3.50 (m, 5H), 3.80 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H),5.6 (s, 1H), 6.94-7.0 (m, 3H), 7.22-7.41 (m, 6H), 7.45-7.64 (m, 4H); MS[M-Br]⁺: 486; mp 157° C.

EXAMPLE 156

1-(3-phenylallyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 250 mg, 94%. ¹H-NMR (CDCl3): δ 1.50-1.60 (m,1H), 1.60-1.80 (m, 1H), 1.90 (m, 2H), 2.30 (m, 1H), 2.65-2.80 (m, 2H),2.90-3.20 (m, 3H), 3.50 (d, 1H), 3.60-3.90 (m, 3H), 4.20 (m, 1H),4.35-4.60 (doble dd, 2H), 5.10 (m, 1H), 5.15 (s, 1H), 6.05 (dd, 1H),6.90-7.0 (m, 2H), 7.0-7.5 (m, 11H); MS [M-Br]⁺: 464; mp 132° C.

EXAMPLE 157

1-(3-phenoxypropyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 290 mg, 94%. ¹H-NMR (CDCl3): δ 1.45-1.60 (m,1H), 1.65-1.80 (m, 1H), 1.80-2.0 (m, 2H), 2.0-2.20 (m, 3H), 2.80-3.0 (m,3H), 3.15-3.30 (m, 2H), 3.30-3.45 (d, 1H), 3.45-3.80 (m, 5H), 3.85-4.0(m, 2H), 4.20 (m, 1H), 5.10 (m, 1H), 5.20 (s, 1H), 6.80-6.90 (d, 2H),6.90-7.0 (t, 1H), 7.10-7.30 (m, 8H), 7.40 (m, 2H); MS [M-Br]⁺: 482; mp182° C.

EXAMPLE 158

3(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 180 mg, 56%. ¹H-NMR (DMSO-d6): δ 1.2 (m, 1H),1.6 (m, 1H), 1.7-1.9 (m, 2H), 1.95 (m, 1H), 2.1 (m, 2H), 2.8 (m, 1H),2.95 (d, 1H), 3.25-3.45 (m, 5H), 3.8 (m, 1H), 4.05 (t, 2H), 4.9 (m, 1H),5.45 (s, 1H), 6.9-7.1 (m, 5H), 7.3-7.5 (m, 9H), 7.55 (d, 2H); MS[M-Br]⁺: 480; mp 1111C.

EXAMPLE 159

3(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;Bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 210 mg, 68%. ¹H-NMR (DMSO-d6): δ 1.2 (m, 1H),1.7-1.9 (m, 2H), 2.0 (m, 1H), 2.85-3.1 (m, 4H), 3.3-3.5 (m, 5H), 3.85(m, 1H), 4.95 (m, 1H), 5.45 (s, 1H), 7.05 (m, 2H), 7.25-7.5 (m, 11H),7.55 (m, 2H); MS [M-Br]⁺: 450; mp 2481C.

The Examples 160 to 164 illustrate pharmaceutical compositions accordingto the present invention and procedure for their preparation.

EXAMPLE 160

Preparation of a pharmaceutical composition: tablets Formulation:Compound of the present invention 5.0 mg Lactose 113.6 mg Microcrystalline cellulose 28.4 mg  Light silicic anhydride 1.5 mgMagnesium stearate 1.5 mg

Using a mixer machine, 15 g of the compound of the present invention wasmixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose.The mixture was subjected to compression moulding using a rollercompactor to give a flake-like compressed material. The flake-likecompressed material was pulverized using a hammer mill, and thepulverized material was screened through a 20 mesh screen. A 4.5 gportion of light silicic anhydride and 4.5 g of magnesium stearate wereadded to the screened material and mixed. The mixer product wassubjected to a tablets making machine equipped with a die/punch systemof 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150mg in weight.

EXAMPLE 161

Preparation of a pharmaceutical composition: tablets coated Formulation:Compound of the present invention 5.0 mg Lactose 95.2 mg  Corn starch40.8 mg  Polyvinylpyrrolidone K25 7.5 mg Magnesium stearate 1.5 mgHydroxypropylcellulose 2.3 mg Polyethylene glycol 6000 0.4 mg Titaniumdioxide 1.1 mg Purified talc 0.7 mg

Using a fluidized bed granulating machine, 15 g of the compound of thepresent invention was mixed with 285.6 g of lactose and 122.4 g of cornstarch. Separately, 22.5 g of polyinylpyrrolidone was dissolved in 127.5g of water to prepare a binding solution. Using a fluidized bedgranulating machine, the binding solution was sprayed on the abovemixture to give granulates. A 4.5 g portion of magnesium stearate wasadded to the obtained granulates and mixed. The obtained mixture wassubjected to a tablet making machine equipped with a die/punch biconcavesystem of 6.5 mm in diameter, thereby obtaining 3,000 tablets, eachhaving 150 mg in weight.

Separately, a coating solution was prepared by suspending 6.9 g ofhydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000,3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water.Using a High Coated, the 3,000 tablets prepared above were coated withthe coating solution to give film-coated tablets, each having 154.5 mgin weight.

EXAMPLE 162

Preparation of a pharmaceutical composition: liquid inhalantFormulation: Compound of the present invention 400 Φg Physiologicalsaline  1 ml

A 40 mg portion of the compound of the present invention was dissolvedin 90 ml of physiological saline, and the solution was adjusted to atotal volume of 100 ml with the same saline solution, dispensed in 1 mlportions into 1 ml capacity ampoule and then sterilized at 1151 for 30minutes to give liquid inhalant.

EXAMPLE 163

Preparation of a pharmaceutical composition: powder inhalantFormulation: Compound of the present invention   200 Φg Lactose 4,000 Φg

A 20 g portion of the compound of the present invention was uniformlymixed with 400 g of lactose, and a 200 mg portion of the mixture waspacked in a powder inhaler for exclusive use to produce a powderinhalant.

EXAMPLE 164

Preparation of a pharmaceutical composition: inhalation aerosol.Formulation: Compound of the present invention   200 Φg Dehydrated(Absolute) ethyl alcohol USP  8,400 Φg 1,1,1,2-Tetrafluoroethane(HFC-134A) 46,810 Φg

The active ingredient concentrate is prepared by dissolving 0.0480 g ofthe compound of the present invention in 2.0160 g of ethyl alcohol. Theconcentrate is added to an appropriate filling apparatus. The activeingredient concentrate is dispensed into aerosol container, theheadspace of the container is purged with Nitrogen or HFC-134A vapor(purging ingredients should not contain more than 1 ppm oxygen) and issealed with valve. 11.2344 g of HFC-134A propellant is then pressurefilled into the sealed container.

What is claimed is:
 1. A compound according to formula (I)

wherein: is a phenyl ring, a C₄ to C₉ heteroaromatic group containingone or more heteroatoms or a naphthalenyl,5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R¹, R² and R³ eachindependently represent a hydrogen atom or halogen atom, or a hydroxygroup, or a phenyl, —OR⁴, —SR⁴, —NR⁴R⁵, —NHCOR⁴, —CONR⁴R⁵, —CN, —NO₂,—COOR⁴ or —CF₃ group, or a straight or branched lower alkyl group whichmay optionally be substituted, for example, with a hydroxy or alkoxygroup, wherein R⁴ and R⁵ each independently represent a hydrogen atom,straight or branched lower alkyl group or together form an alicyclicring; or R¹ and R² together form an aromatic, alicyclic or heterocyclicring, n is an integer from 0 to 4; A represents a —CH₂—, —CH═CR⁶—,—CR⁶═CH—, —CR⁶R⁷—, —CO—, —O—, —S—, —S(O)—, SO₂ or —NR⁶— group, whereinR⁶ and R⁷ each independently represent a hydrogen atom, straight orbranched lower alkyl group or R⁶ and R⁷ together form an alicyclic ring;m is an integer from 0 to 8; provided that when m=0, A is not —CH₂—; pis an integer from 1 to 2 and the substitution in the azoniabicyclicring may be in the 2, 3 or 4 position including all possibleconfigurations of the asymmetric carbons; B represents a group offormula i):

 wherein R¹⁰ represents a hydrogen atom, a hydroxy or methyl group; andR⁸ and R⁹ each independently represent

 wherein R¹¹ represents a hydrogen or halogen atom or a straight orbranched lower alkyl group; and X represents a pharmaceuticallyacceptable anion of a mono or polyvalent acid.
 2. A compound accordingto claim 1, wherein any alkyl group present as R¹ to R⁷ or R¹¹ containsfrom 1 to 4 carbon atoms.
 3. A compound according to claim 1 whereinp=2.
 4. A compound according to claim 1 wherein represents a phenyl,pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl orbenzothiazolyl group.
 5. A compound according to claim 4, whereinrepresents a phenyl, pyrrolyl or thienyl group.
 6. A compound accordingto claim 1 wherein R¹, R² and R³ each independently represent a hydrogenor halogen atom or a hydroxy, methyl, tert-butyl, —CH₂OH,3-hydroxypropyl, —OMe, —NMe₂, —NHCOMe, —CONH₂, —CN, —NO2, —COOMe or —CF₃group.
 7. A compound according to claim 6 wherein R¹, R² and R³ eachindependently represent a hydrogen or halogen atom or a hydroxy group.8. A compound according to claim 7, wherein the halogen atom isfluorine.
 9. A compound according to claim 1 wherein A represents a—CH₂—, —CH═CH—, —CO—, —NH—, —NMe—, —O— or —S— group; n is 0 or 1; and mis an integer from 1 to
 6. 10. A compound according to claim 9, whereinA represents a —CH₂—, —CH═CH— or —O— group and m is 1, 2 or
 3. 11. Acompound according to claim 1 wherein the azoniabicyclo group issubstituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl,3-phenylallyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl,3-(2-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 2-benzyloxyethyl,3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group. 12.A compound according to claim 1 wherein B represents a group of formula(i) and R⁸ and R⁹ each independently represent a phenyl, 2-thienyl,3-thienyl, 2-furyl, or 3-furyl group and R¹¹ represents a hydrogen atom.13. A compound according to claim 1 wherein X represents a bromide,chloride or trifluoroacetate anion.
 14. A compound according to claim 1wherein the azoniabicyclo group is substituted in the 3-position.
 15. Acompound according to claim 14, wherein the substituent in the 3position has (R) configuration.
 16. A compound according to claim 15,wherein R⁸ is different from R⁹ in group i), and the asymmetric carbonto which R⁸ and R⁹ are bonded has the (R) configuration.
 17. A compoundaccording to claim 15, wherein R⁸ is different from R⁹ in group i), andthe asymmetric carbon to which R⁸ and R⁹ are bonded has the (S)configuration.
 18. A compound according to claim 1 which is a singlestereoisomer.
 19. A compound according to claim 1 which is3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane;bromide3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane; bromide3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane; bromide3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane; bromide3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; bromide3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;bromide3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane;bromide1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane; chloride3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-bicyclo[2.2.2]octane;trifluoroacetate3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;bromide3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide.
 20. A compound according to claim 1 characterised in that ithas an IC₅₀ value for muscarinic M₃ receptors (Hm3) of less than 35 nM.21. A process for the preparation of a compound of formula (I)

which comprises reacting an alkylating agent of formula (II)

with a compound of formula (III)

wherein, in each of formulae I, II and III, R¹, R² R³, , A, X, B, n, mand p are as defined in any one of claims 1 to 12 or 13 to
 19. 22. Aprocess according to claim 21 characterised in that the resultingreaction mixture is purified by solid phase extraction.
 23. Apharmaceutical composition comprising a compound according to claim 1 inadmixture with a pharmaceutically acceptable carrier or diluent.
 24. Amethod for treating respiratory, urinary and/or gastrointestinal diseasewhich method comprises administering to a human or animal patient inneed of such treatment an effective amount of a compound according toany one of claims 1 to 12, 13 to 20 or of a pharmaceutical compositionaccording to claim
 23. 25. A method for treating COPD, chronicbronchitis, asthma and/or ehinitis which method comprises administeringto a human or animal patient in need of such treatment an effectiveamount of a compound according to any one of claims 1 to 12, 13 to 20 orof a pharmaceutical composition according to claim 23.